| Therapeutic group . | Anti-C. auris agent . | Mode of action . | Efficacy . | Number of isolates tested . | Reference . |
|---|---|---|---|---|---|
| Antimicrobial combination therapy | Antifungal combinations: echinocandins with azoles (Ongoing clinical trial against non-Candida fungal infection) | Azoles inhibit 14α-demethylase during ergosterol synthesis to compromise cell membrane integrity and lead to accumulation of toxic sterol intermediates. Echinocandins: inhibit glucan synthesis by supressing beta-1,3-D-glucan synthase leading to a compromised cell wall and subsequent cell lysis | Synergy between micafungin and voriconazole fractional inhibitory concentration index (FICI) <0.5. MIC of micafungin single vs. combined (0.125-8 μg/ml 0.016–2 μg/ml); MIC of voriconazole single vs. combined (0.5–8 μg/ml 0.125–1 μg/ml) | 10 | 42 |
| Co-delivery of anidulafungin with voriconazole demonstrated synergy against 5 Candida auris strains and partial synergy against 22 strains. Co-delivery of anidulafungin with isavuconazole demonstrated synergy against 11 Candida auris strains and partial synergy against 19 strains | 36 | 46 | |||
| Antifungal combinations: 5-fluorocytosine with azoles | 5-fluorocytosine inhibits RNA and DNA synthesis by incorporating 5-fluorouracil into fungal RNA. | Improved MIC when 5-fluorocytosine 1 μg/ml combined with voriconazole (>2 μg/ml vs. 0.015 μg/ml) | 13 | 44 | |
| In the presence of 0.91 μM flucytosine, the IC50 value for voriconazole decreased from 7.2 to 2.9 μM. In the presence of 0.55 μM flucytosine, IC50 value of posaconazole decreased from 0.45 to 0.15 μM. | 1 | 45 | |||
| Antifungal combinations: 5-fluorocytosine with echinocandins | Improved MIC when 5-fluorocytosine 1 μg/ml combined with anidulafungin (4 μg/ml vs. 0.0078 μg/ml) caspofungin (2 μg/ml vs. 0.0078 μg/ml) or micafungin (4 μg/ml vs. 0.0078 μg/ml) | 6 | 44 | ||
| Antifungal combinations: 5-fluorocytosine with polyenes | Polyenes: bind to ergosterol in cell membrane leading to pore formation and leakage of cellular cations and anions, and fungal cell death | Improved MIC when 5-fluorocytosine 1 μg/ml combined with amphotericin B (≥2 μg/ml vs. 0.25 μg/ml) | 9 | 44 | |
| Antifungal and antibiotic combinations: azoles with sulfonamides | Sulfamethoxazole inhibits bacterial folate synthesis leading to the inhibition of bacterial purines and DNA synthesis. The mechanism behind its synergy with azoles is not known. | Co-delivery of fluconazole with sulfamethoxazole demonstrated synergy against 1 Candida auris strain (fluconazole MIC 16 μg/ml vs. 4 μg/ml, sulfamethoxazole MIC 512 μg/ml vs. 16 μg/ml) Co-delivery of voriconazole with sulfamethoxazole demonstrated synergy against 3 Candida auris strain (voriconazole MIC 1–8 μg/ml vs. 0.06–2 μg/ml, sulfamethoxazole MIC 512 μg/ml vs. 16–128 μg/ml Co-delivery of itraconazole with sulfamethoxazole demonstrated synergy against 3 Candida auris strain (itraconazole MIC 1–2 μg/ml vs. 0.25–0.31 μg/ml, sulfamethoxazole MIC 512 μg/ml vs. 16-32 μg/ml) | 3 | 47 | |
| Antifungal and antibiotic combinations: azoles with colistin | Colistin affects the bacterial cytoplasmic membrane, changing its permeability and disrupting the cell membrane. The mechanism behind its synergy with azoles is not known. | Co-delivery of isavuconazole and colistin exhibited synergy against Candida auris (isavuconazole MIC 0.004–0.5 μg/ml vs. 0.001–0.25 μg/ml, colistin MIC 128 μg/ml vs. 8–32 μg/ml) | 15 | 50 | |
| Antifungal and non-antimicrobial drug combinations: azoles with pitavastatin | Pitavastatin competitively inhibit HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase, that catalyses the conversion of HMG-CoA to mevalonate, to inhibit cholesterol biosynthesis. The mechanism behind its synergy with azoles is not known. | Co-delivery of fluconazole and pitavastatin exhibited synergy against Candida auris (fluconazole MIC 256 μg/ml vs. 4–16 μg/ml, colistin MIC 64–128 μg/ml vs. 8–32 μg/ml | 5 | 51 | |
| Antifungal and non-antimicrobial drug combinations: azoles with ospemifene | Ospemifene is a selective estrogen receptor modulator that selectively binds to estrogen receptors to stimulate/inhibit the activity of estrogen in humans. Increased activity of itraconazole is likely to be associated with the increased affinity of ospemifene to multidrug efflux pumps | Co-delivery of itraconazole and ospemifene exhibited synergy against Candida auris (itraconazole MIC 0.5-1 μg/ml vs. 0.125–0.25 μg/ml, ospemifene MIC 256 μg/ml vs. 4 μg/ml | 5 | 53 | |
| Antifungal and non-antimicrobial drug combinations: azoles with aprepitant | Aprepitant is an antiemetic that antagonise substance P/neurokinin 1 (NK1) receptors in humans. Azoles with aprepitant combination may affect C. auris membrane transport processes, ions homeostasis and subsequent ROS detoxifying mechanisms and ergosterol biosynthesis, and fungal glucose transport. | Co-delivery of aprepitant with fluconazole (n = 4), itraconazole (n = 8) or voriconazole (n = 2) exhibited synergy against Candida auris (fluconazole MIC 1–256 μg/ml vs. 0.5–8 μg/ml, itraconazole MIC 0.125–1 μg/ml vs. 0.0312–0.125 μg/ml, voriconazole MIC 0.0078–4 μg/ml vs. 0.062 μg/ml aprepitant MIC > 128 μg/ml vs. 0.5–8 μg/ml) | 10 | 52 | |
| Antifungal and non-antimicrobial drug combinations: azoles with lopinavir | Lopinavir inhibits the activity of HIV-1 protease enzyme that is critical for the HIV viral lifecycle. Azoles with lopinavir combination may affect C. auris membrane transport processes, ions homeostasis and subsequent ROS detoxifying mechanisms and ergosterol biosynthesis, and fungal glucose transport. | Co-delivery of lopinavir with fluconazole (n = 3), itraconazole (n = 10) or voriconazole (n = 6) exhibited synergy against Candida auris (fluconazole MIC 1–256 μg/ml vs. 0.25–32 μg/ml, itraconazole MIC 0.125–1 μg/ml vs. 0.00098–0.0078 μg/ml, voriconazole MIC 0.0078–4 μg/ml vs. 0.0156–0.5 μg/ml lopinavir MIC > 128 μg/ml vs. 1–8 μg/ml) | 10 | 54 | |
| Antifungal and non-antimicrobial compounds combinations: 5-fluorocytosine with myriocin | Myriocin is a serine palmitoyltransferase inhibitor that impede sphingolipid biosynthesis in eukaryotic cells. The mechanism behind its synergy with 5-fluorocytosine is not known. | In the presence of 0.55–0.91 μM flucytosine, the IC50 value for Myriocin decreased from 0.63–2.2 μM to 0.18–0.62 μM. | 3 | 45 | |
| Antifungal and non-antimicrobial compounds combinations: antifungal drugs with Neosartorya fischeri antifungal protein 2; NFAP2 | NFAP2 is a small, cysteine-rich, cationic antifungal protein that is likely to kill Candida spp. via membrane disruption. The mechanism behind its synergy with approved antifungals is not known. | Co-delivery of NFAP2 significantly lowered the MBICs of fluconazole (32- to 128-fold), amphotericin B (4- to 64-fold), anidulafungin (16- to 128-fold), caspofungin (4- to 128-fold), and micafungin (64- to 128-fold). | 5 | 56 | |
| Antifungal and antiseptic combinations: Azoles and domiphen bromide | Domiphen bromide is a cationic surfactant which possibly increases the efficacy of azoles by increasing the permeability of the vacuolar membrane, thereby releasing sequestered azoles. | Co-delivery of to 150 μM of miconazole and 37.5 μM domiphen bromide decreased Candida auris biofilm viability by ∼3 Log10 CFUs | 1 | 57 | |
| Antimicrobial peptides | PepBiotics | Interfere with metabolic activity, fungal growth, and/or viability | Complete suppression activity at <1 μM | 1 | 72 |
| lipopeptide-AF4 | Structural homologue of bacillomycin D which induce ion-conducting pores in the lipid component of the fungal cell membranes and subsequent cell death. | Planktonic MIC: 3.48 μg/ml Biofilm MIC: 2-4 folds of planktonic MIC | 10 | 73 | |
| Cm-p5 | Not known. | MIC 11 μg/ml (free form) MIC < 10 μg/ml in hydrogel form | 1 | 77 | |
| Crotamine | Not known. Functional similarities with human β defensins | MIC50 ∼ 40–160 μM | 5 | 80 | |
| θ defensins | Induce oxidative stress and accumulation of ROS within the fungus. | MICs 3.125–6.25 μg/ml | 2 | 96 | |
| Histatin 5 | Likely to act on multiple intracellular targets leading to nonoxidative events such as intracellular ions leakage, ion imbalance, and volume loss accompanied by vacuolar disruption. | MIC90 7.5 μM | 10 | 97 | |
| Ceragenins (CSA131) | Potentially via membrane perturbation, damage via reactive oxygen species (ROS) and attenuation of mitochondrial functions leading to apoptosis | MIC50 0.5–1 μg/ml MIC90 1 μg/ml MBIC50 2–4 μg/ml MBIC80 4–64 μg/ml | 107 (planktonic) 5 (biofilm) | 99,102,103 | |
| Immunotherapy | Anti-CR3-RP polyclonal antibody | Not known | 1;100 dilution; biofilm formation (36–73% inhibition) and established biofilms (28–46% inhibition) | 3 | 106 |
| Anti-Als3p antibody generated via vaccinating mice with NDV-3A vaccine (based on the N-terminus of Als3 protein) | Enhances macrophage-mediated killing, supresses biofilm formation | Sera from NDV-3A-vaccinated mice (1:10 dilution): 40% increase in macrophage mediated Candida auris killing and 40% survival of mice with Candida auris candidemia | 5 | 107 | |
| Human uterine cervical stem cells conditioned medium (hUCESC-CM) | Not known | Up to 56% of growth suppression | 2 | 108 | |
| Metals and nanoparticles | Gallium | Gallium replaces iron in iron containing proteins to alter the functionality of the protein. This leads to arresting the cellular metabolism and growth | MICs 128–256 μg/ml | 8 | 114 |
| Gold(I)−phosphine complexes | Not fully understood. Gold complexes may inhibit mitochondrial functions of the fungus | MIC of chiral square-planar gold(I) complexes MIC 0.98–7.8 μg/ml and MBIC90 3.9 μg/ml for forming biofilms and 7.8–15.6 μg/ml against preformed biofilms | 2 | 118 | |
| Silver nanoparticles (Completed clinical trial against non-Candida fungal infections) | Exact mechanism is not known. They are likely to attach yeast cell surface, increase the cell wall/membrane permeability, and disrupt the cell membrane integrity, leading to cellular apoptosis. In addition, reduction of cell wall ergosterol and hydrolytic enzyme production in other Candida spp. have been noted | IC50 of 0.06 μg/ml (0.06 ppm) for biofilm formation, and 0.48 μg/ml (0.48 ppm) for preformed biofilms | 1 | 123 | |
| MIC < 0.5–1 μg/ml, MFC 1- ≤ 32 μg/ml IC50 of 0.5–4.9 μg/ml for biofilm formation, and 1.2–6.2 μg/ml for preformed biofilms | 10 | 124 | |||
| Bismuth nanoparticles | Exact mechanism is not known. Likely to alter cell membrane permeability. | MIC 1–4 μg/ml; the IC50 for biofilm formation 5.1–113.1 μg/ml | 10 | 129 | |
| Silver nanoparticles with curcumin | Curcumin is shown to downregulate Δ5,6 desaturase (ERG3) leading to significantly lower ergosterol and accumulation of toxic sterol intermediates which leads to cell death. Also reduces proteinase secretion and alter ATPase activity in fungi. | Silver nanoparticles loaded with curcumin: hydroxypropyl-β-cyclodextrin showed significant reduction of Candida auris in disc diffusion assay | 1 | 134 | |
| Ag-Cu-Co trimetallic nanoparticles | Likely to induce cellular apoptosis and subsequent cell necrosis. Also shown to arrest fungal cell cycle | MIC range of 0.39–0.78 μg/ml | 25 | 131 | |
| 10 mg/ml nanoparticles treatment reduced planktonic CFU by 1.49–10.2 log10 and biofilm CFU by 0.98–9.68 log10 | 6 | 138 | |||
| Miscellaneous drugs/compounds | Phenylthiazole compounds | Not known | Planktonic MIC 2 μg/ml >90% reduction in biofilm formation at 2 μg/ml and >50% reduction in preformed biofilms at 8 μg/ml | 8 | 140 |
| Oxadiazolylthiazoles | Not known | Planktonic MIC 2–4 μg/ml | 3 | 141 | |
| MYC-053 | Inhibits chitin synthesis by blocking chitin synthase, leading to defective fungal cell wall and inhibits nucleic acid synthesis in fungi. | IC50 1–4 μg/ml MIC 4 μg/ml | 5 | 142 | |
| VT-1598 (Completed clinical trial against non-Candida fungal infections) | Inhibits the production of ergosterol by acting on the fungal Cyp51 enzyme. | MIC range 0.03–8 μg/ml (MIC50 0.25 μg/ml and MIC90 1 μg/ml) When treated with up to 50 mg/kg, a longer survival rates (>21 days) and lower fungal burdens in the kidneys of neutropenic murine model infected with Candida auris (mean log10 CFU/g, treated vs. control: 3.67 vs7.26) | 100 | 146 | |
| Arylamidine T-2307 | Trigger mitochondrial membrane collapse in fungi. | MIC50 0.008 to 0.015 μg/ml, and 100% inhibition at 0.25 to >4 μg/ml. Significant reductions in kidney CFU in mice treated at 3 mg/kg (mean 5.06 log10 CFU/g) | 23 | 149 | |
| Drimenol | Likely to affect fungal protein secretion, vacuolar functions, chromatin remodelling and cyclin dependent protein kinase (CDK)-associated functions. | MIC 30 μg/ml; complete inhibition MIC 50 μg/ml | 1 | 151 | |
| Cuminaldehyde derivative | Not known. | MIC50 2–15 μg/ml | 1 | 154 | |
| Amidinourease compounds | Not fully understood; may involve in its uptake and intracellular accumulation within the fungus. | MIC 8–64 μg/ml MBIC 128–256 μg/ml | 18 | 155 | |
| Aryl- and heteroaryl-substituted hydrazones | Not fully understood. Likely to interfere with fungal DNA-protein interactions. | MIC 0.015–7.8 μg/ml; significant suppression of biofilm formation at 15.6–31.3 μg/ml | 10 | 156 | |
| Acetohydroxyacid synthase inhibitors | Blocks the acetohydroxyacid synthase leading to the inhibition of branched-chain amino acid biosynthesis pathway. | MIC50 of bensulfuron methyl 0.09 μM MBIC50 of bensulfuron methyl and chlorimuron ethyl 0.596–1.98 μM | 2 | 158 | |
| Natural compounds | Quorum sensing molecules: farnesol | Farnesol is actively involved in ergosterol biosynthesis, induce intracellular ROS, and disrupt mitochondrial functions in several Candida species. The mechanism of anti-C. auris activity is not yet known. May be associated with reduced activity of drug efflux pumps and downregulation of the genes coding for them | Significant reduction of growth rate for up to 12 h when exposed to 50–300 μM. Co-delivery of farnesol with fluconazole (fluconazole MIC50 > 512 μg/ml vs. 64 μg/ml, Farnesol MIC50 300 μM vs. 75 μM), itraconazole (itraconazole MIC50 8–32 μg/ml vs. 0.5 μg/ml, Farnesol MIC50 300 μM vs. 4.69–9.38 μM), voriconazole (voriconazole MIC50 64 μg/ml vs. 0.5 μg/ml, Farnesol MIC50 150–300 μM vs. 4.69–9.38 μM), posaconazole (posaconazole MIC50 16 μg/ml vs. 0.25 μg/ml, Farnesol MIC50 150 μM vs. 2.34 μM) or isavuconazole (isavuconazole MIC50 4–8 μg/ml vs. 0.125 μg/ml, Farnesol MIC50 300 μM vs. 9.38–18.75 μM) exhibited synergy against Candida auris biofilms | 3 | 167 |
| Co-delivery of farnesol with anidulafungin (anidulafungin MIC50 > 64 μg/ml vs. 1 μg/ml, Farnesol MIC50 300 μM vs. 75–150 μM), caspofungin (caspofungin MIC50 8→64 μg/ml vs. 1 μg/ml, Farnesol MIC50 300 μM vs. 9.38–75 μM), or micafungin (micafungin MIC50 > 64 μg/ml vs. 1 μg/ml, Farnesol MIC50 150–300 μM vs. 37.5–75 μM) exhibited synergy against Candida auris biofilms | 4 | 168 | |||
| MIC of farnesol 62.5–125 mM. Farnesol concentrations of 125 mM inhibited Candida auris adhesion, 7.81 mM inhibited >50% of forming biofilms, and 500 mM inhibited 12 h and 24 h biofilms | 25 | 169 | |||
| Chitosan | Not known; may be associated with direct interactions of chitosan with cell surface leading to cell death | Fungicidal concentration for planktonic cells 5–20 μg/ml; biofilm MIC50 10–80 μg/ml and MIC80 40–160 μg/ml | 4 | 23 | |
| Planktonic MIC 5–20 μg/ml biofilm MIC50 10–80 μg/ml and MIC80 40–160 μg/ml. 200 mg of chitosan/kg of body weight increased the survival rate of Galleria mellonella wax warm infected with Candida auris up to 84% | 8 | 172 | |||
| Plant products: Herbal monomers | Not known; likely to be associated with either the cell wall development mechanics and/or the fungal stress response | Planktonic MICs of 64 μg/ml for sodium houttuyfonate, and 50 μg/ml for cinnamaldehyde, 256 μg/ml for berberine, jatrorrhizine, and palmatine | 1 | 179 | |
| Plant products: trans-cinnamaldehyde | Likely to compromise cell membrane and wall integrity | MIC and MFC 0.03% (v/v) | 1 | 182 | |
| Plant products: α-Cyperone | Not known | Growth inhibition at 150 μg/ml | 1 | 184 | |
| Plant products: 6-Shogaol | Not fully understood; likely to act on drug efflux machinery of the fungus | Planktonic MIC50 16–32 μg/ml and MIC80 32–64 μg/ml. >97% of inhibition of forming and preformed biofilms at 64 μg/ml | 5 | 185 | |
| Bee honey | Specific mechanism is not known; antimicrobial activity of honey is associated with its osmotic activity, low pH, the formation of H2O2, and the presence of various phytochemicals. | 40% honey exposure for 24 h reduced Candida auris growth by 2 Log10 | 32 | 189 | |
| Probiotics (Several completed clinical trials against non-auris Candida infections) | Not known; likely to be associated with secondary metabolite(s) produced by the probiotic yeasts that interfere the pathogen's life cycle; secreted probiotic short-chain fatty acids or bacteriocins or competitive inhibition of the pathogen during attachment. | Significant inhibition of Candida auris (up to 6 log10 CFU) when co-cultured with Lactobacillus paracasei 28.4 or exposed to crude extracts of the lactobacilli supernatant (>15 mg/ml) and its first fraction (3.75– >7.5 mg/ml) | 10 | 192 | |
| Co-inoculation of Candida auris strains with Saccharomyces cerevisiae and Issatchenkia occidentali resulted a 44–62% reduction in C. auris adhesion | 5 | 193 | |||
| Novel antifungal compounds | Ibrexafungerp (SCY-078) (Phase 3 clinical trial; ClinicalTrials.gov Identifier: NCT03363841) | A triterpene glucan synthase inhibitor that inhibits the synthesis of β-1,3-glucan synthase leading to defective cell wall. | MIC 0.0625–2 μg/ml (mode MIC50 0.5 μg/ml and MIC90 1 μg/ml) | 100 | 196 |
| MIC 0.06–8 μg/ml (mode MIC50 0.5 μg/ml) | 200 | 197 | |||
| MIC90 1 μg/ml; significant reduction of the viability and thickness of biofilms when exposed to 4 μg/ml of ibrexafungerp | 16 | 198 | |||
| modal MIC and MIC50 of 0.5 μg/ml (a range of 0.06–2 μg/ml) | 122 | 200 | |||
| SCY-247 | Analog of SCY-078 that inhibits the synthesis of β-1,3-glucan synthase leading to defective cell wall | MIC range 0.06–1 μg/ml (MIC50 and MIC90 0.5 μg/ml). MFC range 0.5–8 μg/ml (MFC50 and MFC90 of 4 μg/ml) | 44 | 204 | |
| Fosmanogepix (APX001/APX001A) (Phase 2 clinical trial; ClinicalTrials.gov Identifier: NCT04148287) | Targets a highly conserved fungal enzyme Gwt1 that catalyses the inositol acylation step of glycosylphosphatidylinositol (GPI) anchored cell wall mannoproteins synthesis. This in turn affects maturation and localization of fungal cell wall mannoproteins, leading to compromised cell wall integrity, defective filamentation and biofilm formation, and severe defects in fungal growth. | MIC50 0.004 μg/ml and MIC90 0.031 μg/ml the exposure of APX001 significantly increased the 16-day survival rate of Candida auris infected immunocompromised mice. | 16 | 208 | |
| MIC50 range < 0.005–0.015 μg/ml (overall modal MIC 0.005 μg/ml, MIC50 0.002 μg/ml and MIC90 0.008 μg/ml) | 100 | 209 | |||
| MIC50 range 0.001–0.125 μg/ml (MIC50 0.016 μg/ml and MIC90 0.03 μg/ml) | 122 | 210 | |||
| Rezafungin (CD101) (Currently on clinical trials against invasive candidiasis; Causative organism unspecified. | Similar to echinocandins | MIC range 0.03–8 μg/ml (mode MIC50 0.125 μg/ml, MIC90 0.5 μg/ml) | 100 | 218 | |
| MIC range 0.06–16 μg/ml (MIC50 0.25 μg/ml, MIC90 1 μg/ml) | 122 | 220 | |||
| Significant reduction of Candida auris in kidney tissues of mice with disseminated Candida auris candidiasis when treated with rezafungin 20 mg/kg intraperitoneally at Day 0, 3 and 6. intravenously administration of rezafungin 400 mg/once a week would likely to meet or exceed the pharmacodynamics target for >90% of C. auris isolates | 4 | 222,223 | |||
| PC945 (Currently on clinical trials against Candida lung infections; Causative organism unspecified.) | Acts on ergosterol synthesis pathway by inhibiting lanosterol 14a-demethylase enzyme coded by ERG11. | MIC50 0.063 μg/ml and MIC90 0.25 μg/ml | 72 | 224 | |
| Ebselen | Not fully understood. It is considered an antioxidant that mimic glutathione peroxidase activity and catalyse the reduction of ROS, leading to the attenuation of damage caused by oxidants and radicals. | Planktonic IC50 0.2345–1.47 μg/ml, complete inhibition at 2.5 μM Biofilm IC50 5.864–9.781 μg/ml | 10 | 225 | |
| Suloctidil | Not fully understood. It may act as an inhibitor of thromboxane synthase or as a thromboxane receptor antagonist. | 16 μg/ml inhibited Candida auris growth by >78% (MIC50 4–8 μg/ml, MIC90 4–16 μg/ml) | 7 | 230 | |
| miltefosine | Not known. Miltefosine is an alkylphosphocholine drug originally developed as an anti-cancer drug. It may inhibit cytochrome-c oxidase within mitochondria leading to mitochondrial dysfunction and apoptosis-like cell death. | Complete elimination of planktonic growth and biofilms formation at 4 μg/ml. a 90% reduction of viability of preformed biofilms at 16 μg/ml. IC50 for Planktonic phase 0.9237–2.472 μg/ml, biofilm formation 1.158–6.049 μg/ml, preformed biofilms 9.144–20.98 μg/ml | 10 | 231 | |
| Iodoquinol | Not known | Complete elimination of planktonic growth at 4 μg/ml IC50 for Planktonic phase 0.2972–2.006 μg/ml, biofilm formation 9.159–56.02 μg/ml, preformed biofilms 38.58- >64 μg/ml | 10 | 231 | |
| Niclosamide and halogenated salicylanilide | An Anthelmintic drug. They are likely to interfere morphological transition and mitochondrial protein import machinery. | Both compounds inhibited Candida auris biofilms at 1 μM | 1 | 233 | |
| Repurposed drugs | Disulfiram | Disulfiram blocks the oxidation of alcohol by irreversibly inactivation aldehyde dehydrogenase in human cells. This results in an accumulation of acetaldehyde in the blood causing highly unpleasant symptoms. Mechanism of antifungal effect is not known. | MIC50 1 μg/ml, MIC80 4–8 μg/ml MBIC80 64–128 μg/ml | 2 | 234 |
| Sertraline (Currently on clinical trials against non-Candida infections) | Sertraline is likely to elicit its effect of C. auris by binding to the Erg11p in the ergosterol biosynthesis pathway. | MIC 20–40 μg/ml; a 71% inhibition of biofilm formation at 20 μg/ml | 3 | 235 | |
| Alexidine dihydrochloride | Targets PTPMT, a mitochondrial tyrosine phosphatase in mammalian cells to drive mitochondrial apoptosis. Mechanism of antifungal effect is not known. | MIC50 0.73–1.5 μg/ml, MIC80 1.5 μg/ml Biofilm formation and mature biofilm inhibition concentrations: MBIC50 and MBIC80 3–6 μg/ml | 2 | 238 | |
| Mefloquine derivatives | Antifungal activity is likely to be due to the disruption of the mitochondrial membrane, interference with mitochondrial DNA stability and disruption vacuoles. | Planktonic MIC 2–8 μg/ml Planktonic MIC against fluconazole resistant isolates 4–16 μg/ml | 5 | 242 |
| Therapeutic group . | Anti-C. auris agent . | Mode of action . | Efficacy . | Number of isolates tested . | Reference . |
|---|---|---|---|---|---|
| Antimicrobial combination therapy | Antifungal combinations: echinocandins with azoles (Ongoing clinical trial against non-Candida fungal infection) | Azoles inhibit 14α-demethylase during ergosterol synthesis to compromise cell membrane integrity and lead to accumulation of toxic sterol intermediates. Echinocandins: inhibit glucan synthesis by supressing beta-1,3-D-glucan synthase leading to a compromised cell wall and subsequent cell lysis | Synergy between micafungin and voriconazole fractional inhibitory concentration index (FICI) <0.5. MIC of micafungin single vs. combined (0.125-8 μg/ml 0.016–2 μg/ml); MIC of voriconazole single vs. combined (0.5–8 μg/ml 0.125–1 μg/ml) | 10 | 42 |
| Co-delivery of anidulafungin with voriconazole demonstrated synergy against 5 Candida auris strains and partial synergy against 22 strains. Co-delivery of anidulafungin with isavuconazole demonstrated synergy against 11 Candida auris strains and partial synergy against 19 strains | 36 | 46 | |||
| Antifungal combinations: 5-fluorocytosine with azoles | 5-fluorocytosine inhibits RNA and DNA synthesis by incorporating 5-fluorouracil into fungal RNA. | Improved MIC when 5-fluorocytosine 1 μg/ml combined with voriconazole (>2 μg/ml vs. 0.015 μg/ml) | 13 | 44 | |
| In the presence of 0.91 μM flucytosine, the IC50 value for voriconazole decreased from 7.2 to 2.9 μM. In the presence of 0.55 μM flucytosine, IC50 value of posaconazole decreased from 0.45 to 0.15 μM. | 1 | 45 | |||
| Antifungal combinations: 5-fluorocytosine with echinocandins | Improved MIC when 5-fluorocytosine 1 μg/ml combined with anidulafungin (4 μg/ml vs. 0.0078 μg/ml) caspofungin (2 μg/ml vs. 0.0078 μg/ml) or micafungin (4 μg/ml vs. 0.0078 μg/ml) | 6 | 44 | ||
| Antifungal combinations: 5-fluorocytosine with polyenes | Polyenes: bind to ergosterol in cell membrane leading to pore formation and leakage of cellular cations and anions, and fungal cell death | Improved MIC when 5-fluorocytosine 1 μg/ml combined with amphotericin B (≥2 μg/ml vs. 0.25 μg/ml) | 9 | 44 | |
| Antifungal and antibiotic combinations: azoles with sulfonamides | Sulfamethoxazole inhibits bacterial folate synthesis leading to the inhibition of bacterial purines and DNA synthesis. The mechanism behind its synergy with azoles is not known. | Co-delivery of fluconazole with sulfamethoxazole demonstrated synergy against 1 Candida auris strain (fluconazole MIC 16 μg/ml vs. 4 μg/ml, sulfamethoxazole MIC 512 μg/ml vs. 16 μg/ml) Co-delivery of voriconazole with sulfamethoxazole demonstrated synergy against 3 Candida auris strain (voriconazole MIC 1–8 μg/ml vs. 0.06–2 μg/ml, sulfamethoxazole MIC 512 μg/ml vs. 16–128 μg/ml Co-delivery of itraconazole with sulfamethoxazole demonstrated synergy against 3 Candida auris strain (itraconazole MIC 1–2 μg/ml vs. 0.25–0.31 μg/ml, sulfamethoxazole MIC 512 μg/ml vs. 16-32 μg/ml) | 3 | 47 | |
| Antifungal and antibiotic combinations: azoles with colistin | Colistin affects the bacterial cytoplasmic membrane, changing its permeability and disrupting the cell membrane. The mechanism behind its synergy with azoles is not known. | Co-delivery of isavuconazole and colistin exhibited synergy against Candida auris (isavuconazole MIC 0.004–0.5 μg/ml vs. 0.001–0.25 μg/ml, colistin MIC 128 μg/ml vs. 8–32 μg/ml) | 15 | 50 | |
| Antifungal and non-antimicrobial drug combinations: azoles with pitavastatin | Pitavastatin competitively inhibit HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase, that catalyses the conversion of HMG-CoA to mevalonate, to inhibit cholesterol biosynthesis. The mechanism behind its synergy with azoles is not known. | Co-delivery of fluconazole and pitavastatin exhibited synergy against Candida auris (fluconazole MIC 256 μg/ml vs. 4–16 μg/ml, colistin MIC 64–128 μg/ml vs. 8–32 μg/ml | 5 | 51 | |
| Antifungal and non-antimicrobial drug combinations: azoles with ospemifene | Ospemifene is a selective estrogen receptor modulator that selectively binds to estrogen receptors to stimulate/inhibit the activity of estrogen in humans. Increased activity of itraconazole is likely to be associated with the increased affinity of ospemifene to multidrug efflux pumps | Co-delivery of itraconazole and ospemifene exhibited synergy against Candida auris (itraconazole MIC 0.5-1 μg/ml vs. 0.125–0.25 μg/ml, ospemifene MIC 256 μg/ml vs. 4 μg/ml | 5 | 53 | |
| Antifungal and non-antimicrobial drug combinations: azoles with aprepitant | Aprepitant is an antiemetic that antagonise substance P/neurokinin 1 (NK1) receptors in humans. Azoles with aprepitant combination may affect C. auris membrane transport processes, ions homeostasis and subsequent ROS detoxifying mechanisms and ergosterol biosynthesis, and fungal glucose transport. | Co-delivery of aprepitant with fluconazole (n = 4), itraconazole (n = 8) or voriconazole (n = 2) exhibited synergy against Candida auris (fluconazole MIC 1–256 μg/ml vs. 0.5–8 μg/ml, itraconazole MIC 0.125–1 μg/ml vs. 0.0312–0.125 μg/ml, voriconazole MIC 0.0078–4 μg/ml vs. 0.062 μg/ml aprepitant MIC > 128 μg/ml vs. 0.5–8 μg/ml) | 10 | 52 | |
| Antifungal and non-antimicrobial drug combinations: azoles with lopinavir | Lopinavir inhibits the activity of HIV-1 protease enzyme that is critical for the HIV viral lifecycle. Azoles with lopinavir combination may affect C. auris membrane transport processes, ions homeostasis and subsequent ROS detoxifying mechanisms and ergosterol biosynthesis, and fungal glucose transport. | Co-delivery of lopinavir with fluconazole (n = 3), itraconazole (n = 10) or voriconazole (n = 6) exhibited synergy against Candida auris (fluconazole MIC 1–256 μg/ml vs. 0.25–32 μg/ml, itraconazole MIC 0.125–1 μg/ml vs. 0.00098–0.0078 μg/ml, voriconazole MIC 0.0078–4 μg/ml vs. 0.0156–0.5 μg/ml lopinavir MIC > 128 μg/ml vs. 1–8 μg/ml) | 10 | 54 | |
| Antifungal and non-antimicrobial compounds combinations: 5-fluorocytosine with myriocin | Myriocin is a serine palmitoyltransferase inhibitor that impede sphingolipid biosynthesis in eukaryotic cells. The mechanism behind its synergy with 5-fluorocytosine is not known. | In the presence of 0.55–0.91 μM flucytosine, the IC50 value for Myriocin decreased from 0.63–2.2 μM to 0.18–0.62 μM. | 3 | 45 | |
| Antifungal and non-antimicrobial compounds combinations: antifungal drugs with Neosartorya fischeri antifungal protein 2; NFAP2 | NFAP2 is a small, cysteine-rich, cationic antifungal protein that is likely to kill Candida spp. via membrane disruption. The mechanism behind its synergy with approved antifungals is not known. | Co-delivery of NFAP2 significantly lowered the MBICs of fluconazole (32- to 128-fold), amphotericin B (4- to 64-fold), anidulafungin (16- to 128-fold), caspofungin (4- to 128-fold), and micafungin (64- to 128-fold). | 5 | 56 | |
| Antifungal and antiseptic combinations: Azoles and domiphen bromide | Domiphen bromide is a cationic surfactant which possibly increases the efficacy of azoles by increasing the permeability of the vacuolar membrane, thereby releasing sequestered azoles. | Co-delivery of to 150 μM of miconazole and 37.5 μM domiphen bromide decreased Candida auris biofilm viability by ∼3 Log10 CFUs | 1 | 57 | |
| Antimicrobial peptides | PepBiotics | Interfere with metabolic activity, fungal growth, and/or viability | Complete suppression activity at <1 μM | 1 | 72 |
| lipopeptide-AF4 | Structural homologue of bacillomycin D which induce ion-conducting pores in the lipid component of the fungal cell membranes and subsequent cell death. | Planktonic MIC: 3.48 μg/ml Biofilm MIC: 2-4 folds of planktonic MIC | 10 | 73 | |
| Cm-p5 | Not known. | MIC 11 μg/ml (free form) MIC < 10 μg/ml in hydrogel form | 1 | 77 | |
| Crotamine | Not known. Functional similarities with human β defensins | MIC50 ∼ 40–160 μM | 5 | 80 | |
| θ defensins | Induce oxidative stress and accumulation of ROS within the fungus. | MICs 3.125–6.25 μg/ml | 2 | 96 | |
| Histatin 5 | Likely to act on multiple intracellular targets leading to nonoxidative events such as intracellular ions leakage, ion imbalance, and volume loss accompanied by vacuolar disruption. | MIC90 7.5 μM | 10 | 97 | |
| Ceragenins (CSA131) | Potentially via membrane perturbation, damage via reactive oxygen species (ROS) and attenuation of mitochondrial functions leading to apoptosis | MIC50 0.5–1 μg/ml MIC90 1 μg/ml MBIC50 2–4 μg/ml MBIC80 4–64 μg/ml | 107 (planktonic) 5 (biofilm) | 99,102,103 | |
| Immunotherapy | Anti-CR3-RP polyclonal antibody | Not known | 1;100 dilution; biofilm formation (36–73% inhibition) and established biofilms (28–46% inhibition) | 3 | 106 |
| Anti-Als3p antibody generated via vaccinating mice with NDV-3A vaccine (based on the N-terminus of Als3 protein) | Enhances macrophage-mediated killing, supresses biofilm formation | Sera from NDV-3A-vaccinated mice (1:10 dilution): 40% increase in macrophage mediated Candida auris killing and 40% survival of mice with Candida auris candidemia | 5 | 107 | |
| Human uterine cervical stem cells conditioned medium (hUCESC-CM) | Not known | Up to 56% of growth suppression | 2 | 108 | |
| Metals and nanoparticles | Gallium | Gallium replaces iron in iron containing proteins to alter the functionality of the protein. This leads to arresting the cellular metabolism and growth | MICs 128–256 μg/ml | 8 | 114 |
| Gold(I)−phosphine complexes | Not fully understood. Gold complexes may inhibit mitochondrial functions of the fungus | MIC of chiral square-planar gold(I) complexes MIC 0.98–7.8 μg/ml and MBIC90 3.9 μg/ml for forming biofilms and 7.8–15.6 μg/ml against preformed biofilms | 2 | 118 | |
| Silver nanoparticles (Completed clinical trial against non-Candida fungal infections) | Exact mechanism is not known. They are likely to attach yeast cell surface, increase the cell wall/membrane permeability, and disrupt the cell membrane integrity, leading to cellular apoptosis. In addition, reduction of cell wall ergosterol and hydrolytic enzyme production in other Candida spp. have been noted | IC50 of 0.06 μg/ml (0.06 ppm) for biofilm formation, and 0.48 μg/ml (0.48 ppm) for preformed biofilms | 1 | 123 | |
| MIC < 0.5–1 μg/ml, MFC 1- ≤ 32 μg/ml IC50 of 0.5–4.9 μg/ml for biofilm formation, and 1.2–6.2 μg/ml for preformed biofilms | 10 | 124 | |||
| Bismuth nanoparticles | Exact mechanism is not known. Likely to alter cell membrane permeability. | MIC 1–4 μg/ml; the IC50 for biofilm formation 5.1–113.1 μg/ml | 10 | 129 | |
| Silver nanoparticles with curcumin | Curcumin is shown to downregulate Δ5,6 desaturase (ERG3) leading to significantly lower ergosterol and accumulation of toxic sterol intermediates which leads to cell death. Also reduces proteinase secretion and alter ATPase activity in fungi. | Silver nanoparticles loaded with curcumin: hydroxypropyl-β-cyclodextrin showed significant reduction of Candida auris in disc diffusion assay | 1 | 134 | |
| Ag-Cu-Co trimetallic nanoparticles | Likely to induce cellular apoptosis and subsequent cell necrosis. Also shown to arrest fungal cell cycle | MIC range of 0.39–0.78 μg/ml | 25 | 131 | |
| 10 mg/ml nanoparticles treatment reduced planktonic CFU by 1.49–10.2 log10 and biofilm CFU by 0.98–9.68 log10 | 6 | 138 | |||
| Miscellaneous drugs/compounds | Phenylthiazole compounds | Not known | Planktonic MIC 2 μg/ml >90% reduction in biofilm formation at 2 μg/ml and >50% reduction in preformed biofilms at 8 μg/ml | 8 | 140 |
| Oxadiazolylthiazoles | Not known | Planktonic MIC 2–4 μg/ml | 3 | 141 | |
| MYC-053 | Inhibits chitin synthesis by blocking chitin synthase, leading to defective fungal cell wall and inhibits nucleic acid synthesis in fungi. | IC50 1–4 μg/ml MIC 4 μg/ml | 5 | 142 | |
| VT-1598 (Completed clinical trial against non-Candida fungal infections) | Inhibits the production of ergosterol by acting on the fungal Cyp51 enzyme. | MIC range 0.03–8 μg/ml (MIC50 0.25 μg/ml and MIC90 1 μg/ml) When treated with up to 50 mg/kg, a longer survival rates (>21 days) and lower fungal burdens in the kidneys of neutropenic murine model infected with Candida auris (mean log10 CFU/g, treated vs. control: 3.67 vs7.26) | 100 | 146 | |
| Arylamidine T-2307 | Trigger mitochondrial membrane collapse in fungi. | MIC50 0.008 to 0.015 μg/ml, and 100% inhibition at 0.25 to >4 μg/ml. Significant reductions in kidney CFU in mice treated at 3 mg/kg (mean 5.06 log10 CFU/g) | 23 | 149 | |
| Drimenol | Likely to affect fungal protein secretion, vacuolar functions, chromatin remodelling and cyclin dependent protein kinase (CDK)-associated functions. | MIC 30 μg/ml; complete inhibition MIC 50 μg/ml | 1 | 151 | |
| Cuminaldehyde derivative | Not known. | MIC50 2–15 μg/ml | 1 | 154 | |
| Amidinourease compounds | Not fully understood; may involve in its uptake and intracellular accumulation within the fungus. | MIC 8–64 μg/ml MBIC 128–256 μg/ml | 18 | 155 | |
| Aryl- and heteroaryl-substituted hydrazones | Not fully understood. Likely to interfere with fungal DNA-protein interactions. | MIC 0.015–7.8 μg/ml; significant suppression of biofilm formation at 15.6–31.3 μg/ml | 10 | 156 | |
| Acetohydroxyacid synthase inhibitors | Blocks the acetohydroxyacid synthase leading to the inhibition of branched-chain amino acid biosynthesis pathway. | MIC50 of bensulfuron methyl 0.09 μM MBIC50 of bensulfuron methyl and chlorimuron ethyl 0.596–1.98 μM | 2 | 158 | |
| Natural compounds | Quorum sensing molecules: farnesol | Farnesol is actively involved in ergosterol biosynthesis, induce intracellular ROS, and disrupt mitochondrial functions in several Candida species. The mechanism of anti-C. auris activity is not yet known. May be associated with reduced activity of drug efflux pumps and downregulation of the genes coding for them | Significant reduction of growth rate for up to 12 h when exposed to 50–300 μM. Co-delivery of farnesol with fluconazole (fluconazole MIC50 > 512 μg/ml vs. 64 μg/ml, Farnesol MIC50 300 μM vs. 75 μM), itraconazole (itraconazole MIC50 8–32 μg/ml vs. 0.5 μg/ml, Farnesol MIC50 300 μM vs. 4.69–9.38 μM), voriconazole (voriconazole MIC50 64 μg/ml vs. 0.5 μg/ml, Farnesol MIC50 150–300 μM vs. 4.69–9.38 μM), posaconazole (posaconazole MIC50 16 μg/ml vs. 0.25 μg/ml, Farnesol MIC50 150 μM vs. 2.34 μM) or isavuconazole (isavuconazole MIC50 4–8 μg/ml vs. 0.125 μg/ml, Farnesol MIC50 300 μM vs. 9.38–18.75 μM) exhibited synergy against Candida auris biofilms | 3 | 167 |
| Co-delivery of farnesol with anidulafungin (anidulafungin MIC50 > 64 μg/ml vs. 1 μg/ml, Farnesol MIC50 300 μM vs. 75–150 μM), caspofungin (caspofungin MIC50 8→64 μg/ml vs. 1 μg/ml, Farnesol MIC50 300 μM vs. 9.38–75 μM), or micafungin (micafungin MIC50 > 64 μg/ml vs. 1 μg/ml, Farnesol MIC50 150–300 μM vs. 37.5–75 μM) exhibited synergy against Candida auris biofilms | 4 | 168 | |||
| MIC of farnesol 62.5–125 mM. Farnesol concentrations of 125 mM inhibited Candida auris adhesion, 7.81 mM inhibited >50% of forming biofilms, and 500 mM inhibited 12 h and 24 h biofilms | 25 | 169 | |||
| Chitosan | Not known; may be associated with direct interactions of chitosan with cell surface leading to cell death | Fungicidal concentration for planktonic cells 5–20 μg/ml; biofilm MIC50 10–80 μg/ml and MIC80 40–160 μg/ml | 4 | 23 | |
| Planktonic MIC 5–20 μg/ml biofilm MIC50 10–80 μg/ml and MIC80 40–160 μg/ml. 200 mg of chitosan/kg of body weight increased the survival rate of Galleria mellonella wax warm infected with Candida auris up to 84% | 8 | 172 | |||
| Plant products: Herbal monomers | Not known; likely to be associated with either the cell wall development mechanics and/or the fungal stress response | Planktonic MICs of 64 μg/ml for sodium houttuyfonate, and 50 μg/ml for cinnamaldehyde, 256 μg/ml for berberine, jatrorrhizine, and palmatine | 1 | 179 | |
| Plant products: trans-cinnamaldehyde | Likely to compromise cell membrane and wall integrity | MIC and MFC 0.03% (v/v) | 1 | 182 | |
| Plant products: α-Cyperone | Not known | Growth inhibition at 150 μg/ml | 1 | 184 | |
| Plant products: 6-Shogaol | Not fully understood; likely to act on drug efflux machinery of the fungus | Planktonic MIC50 16–32 μg/ml and MIC80 32–64 μg/ml. >97% of inhibition of forming and preformed biofilms at 64 μg/ml | 5 | 185 | |
| Bee honey | Specific mechanism is not known; antimicrobial activity of honey is associated with its osmotic activity, low pH, the formation of H2O2, and the presence of various phytochemicals. | 40% honey exposure for 24 h reduced Candida auris growth by 2 Log10 | 32 | 189 | |
| Probiotics (Several completed clinical trials against non-auris Candida infections) | Not known; likely to be associated with secondary metabolite(s) produced by the probiotic yeasts that interfere the pathogen's life cycle; secreted probiotic short-chain fatty acids or bacteriocins or competitive inhibition of the pathogen during attachment. | Significant inhibition of Candida auris (up to 6 log10 CFU) when co-cultured with Lactobacillus paracasei 28.4 or exposed to crude extracts of the lactobacilli supernatant (>15 mg/ml) and its first fraction (3.75– >7.5 mg/ml) | 10 | 192 | |
| Co-inoculation of Candida auris strains with Saccharomyces cerevisiae and Issatchenkia occidentali resulted a 44–62% reduction in C. auris adhesion | 5 | 193 | |||
| Novel antifungal compounds | Ibrexafungerp (SCY-078) (Phase 3 clinical trial; ClinicalTrials.gov Identifier: NCT03363841) | A triterpene glucan synthase inhibitor that inhibits the synthesis of β-1,3-glucan synthase leading to defective cell wall. | MIC 0.0625–2 μg/ml (mode MIC50 0.5 μg/ml and MIC90 1 μg/ml) | 100 | 196 |
| MIC 0.06–8 μg/ml (mode MIC50 0.5 μg/ml) | 200 | 197 | |||
| MIC90 1 μg/ml; significant reduction of the viability and thickness of biofilms when exposed to 4 μg/ml of ibrexafungerp | 16 | 198 | |||
| modal MIC and MIC50 of 0.5 μg/ml (a range of 0.06–2 μg/ml) | 122 | 200 | |||
| SCY-247 | Analog of SCY-078 that inhibits the synthesis of β-1,3-glucan synthase leading to defective cell wall | MIC range 0.06–1 μg/ml (MIC50 and MIC90 0.5 μg/ml). MFC range 0.5–8 μg/ml (MFC50 and MFC90 of 4 μg/ml) | 44 | 204 | |
| Fosmanogepix (APX001/APX001A) (Phase 2 clinical trial; ClinicalTrials.gov Identifier: NCT04148287) | Targets a highly conserved fungal enzyme Gwt1 that catalyses the inositol acylation step of glycosylphosphatidylinositol (GPI) anchored cell wall mannoproteins synthesis. This in turn affects maturation and localization of fungal cell wall mannoproteins, leading to compromised cell wall integrity, defective filamentation and biofilm formation, and severe defects in fungal growth. | MIC50 0.004 μg/ml and MIC90 0.031 μg/ml the exposure of APX001 significantly increased the 16-day survival rate of Candida auris infected immunocompromised mice. | 16 | 208 | |
| MIC50 range < 0.005–0.015 μg/ml (overall modal MIC 0.005 μg/ml, MIC50 0.002 μg/ml and MIC90 0.008 μg/ml) | 100 | 209 | |||
| MIC50 range 0.001–0.125 μg/ml (MIC50 0.016 μg/ml and MIC90 0.03 μg/ml) | 122 | 210 | |||
| Rezafungin (CD101) (Currently on clinical trials against invasive candidiasis; Causative organism unspecified. | Similar to echinocandins | MIC range 0.03–8 μg/ml (mode MIC50 0.125 μg/ml, MIC90 0.5 μg/ml) | 100 | 218 | |
| MIC range 0.06–16 μg/ml (MIC50 0.25 μg/ml, MIC90 1 μg/ml) | 122 | 220 | |||
| Significant reduction of Candida auris in kidney tissues of mice with disseminated Candida auris candidiasis when treated with rezafungin 20 mg/kg intraperitoneally at Day 0, 3 and 6. intravenously administration of rezafungin 400 mg/once a week would likely to meet or exceed the pharmacodynamics target for >90% of C. auris isolates | 4 | 222,223 | |||
| PC945 (Currently on clinical trials against Candida lung infections; Causative organism unspecified.) | Acts on ergosterol synthesis pathway by inhibiting lanosterol 14a-demethylase enzyme coded by ERG11. | MIC50 0.063 μg/ml and MIC90 0.25 μg/ml | 72 | 224 | |
| Ebselen | Not fully understood. It is considered an antioxidant that mimic glutathione peroxidase activity and catalyse the reduction of ROS, leading to the attenuation of damage caused by oxidants and radicals. | Planktonic IC50 0.2345–1.47 μg/ml, complete inhibition at 2.5 μM Biofilm IC50 5.864–9.781 μg/ml | 10 | 225 | |
| Suloctidil | Not fully understood. It may act as an inhibitor of thromboxane synthase or as a thromboxane receptor antagonist. | 16 μg/ml inhibited Candida auris growth by >78% (MIC50 4–8 μg/ml, MIC90 4–16 μg/ml) | 7 | 230 | |
| miltefosine | Not known. Miltefosine is an alkylphosphocholine drug originally developed as an anti-cancer drug. It may inhibit cytochrome-c oxidase within mitochondria leading to mitochondrial dysfunction and apoptosis-like cell death. | Complete elimination of planktonic growth and biofilms formation at 4 μg/ml. a 90% reduction of viability of preformed biofilms at 16 μg/ml. IC50 for Planktonic phase 0.9237–2.472 μg/ml, biofilm formation 1.158–6.049 μg/ml, preformed biofilms 9.144–20.98 μg/ml | 10 | 231 | |
| Iodoquinol | Not known | Complete elimination of planktonic growth at 4 μg/ml IC50 for Planktonic phase 0.2972–2.006 μg/ml, biofilm formation 9.159–56.02 μg/ml, preformed biofilms 38.58- >64 μg/ml | 10 | 231 | |
| Niclosamide and halogenated salicylanilide | An Anthelmintic drug. They are likely to interfere morphological transition and mitochondrial protein import machinery. | Both compounds inhibited Candida auris biofilms at 1 μM | 1 | 233 | |
| Repurposed drugs | Disulfiram | Disulfiram blocks the oxidation of alcohol by irreversibly inactivation aldehyde dehydrogenase in human cells. This results in an accumulation of acetaldehyde in the blood causing highly unpleasant symptoms. Mechanism of antifungal effect is not known. | MIC50 1 μg/ml, MIC80 4–8 μg/ml MBIC80 64–128 μg/ml | 2 | 234 |
| Sertraline (Currently on clinical trials against non-Candida infections) | Sertraline is likely to elicit its effect of C. auris by binding to the Erg11p in the ergosterol biosynthesis pathway. | MIC 20–40 μg/ml; a 71% inhibition of biofilm formation at 20 μg/ml | 3 | 235 | |
| Alexidine dihydrochloride | Targets PTPMT, a mitochondrial tyrosine phosphatase in mammalian cells to drive mitochondrial apoptosis. Mechanism of antifungal effect is not known. | MIC50 0.73–1.5 μg/ml, MIC80 1.5 μg/ml Biofilm formation and mature biofilm inhibition concentrations: MBIC50 and MBIC80 3–6 μg/ml | 2 | 238 | |
| Mefloquine derivatives | Antifungal activity is likely to be due to the disruption of the mitochondrial membrane, interference with mitochondrial DNA stability and disruption vacuoles. | Planktonic MIC 2–8 μg/ml Planktonic MIC against fluconazole resistant isolates 4–16 μg/ml | 5 | 242 |
FICI: Fractional inhibitory concentration index, MIC: Minimum inhibitory concentration, IC50: 50% of maximum inhibitory concentration, ROS: Reactive oxygen species, CFU: Colony forming units, ATP: Adenosine triphosphate, MBIC50: The Minimal Biofilm Inhibition Concentration 50%, MBIC80: The Minimal Biofilm Inhibition Concentration 80%, MBIC90: The Minimal Biofilm Inhibition Concentration 90%, UV-C: Ultraviolet light -C.
| Therapeutic group . | Anti-C. auris agent . | Mode of action . | Efficacy . | Number of isolates tested . | Reference . |
|---|---|---|---|---|---|
| Antimicrobial combination therapy | Antifungal combinations: echinocandins with azoles (Ongoing clinical trial against non-Candida fungal infection) | Azoles inhibit 14α-demethylase during ergosterol synthesis to compromise cell membrane integrity and lead to accumulation of toxic sterol intermediates. Echinocandins: inhibit glucan synthesis by supressing beta-1,3-D-glucan synthase leading to a compromised cell wall and subsequent cell lysis | Synergy between micafungin and voriconazole fractional inhibitory concentration index (FICI) <0.5. MIC of micafungin single vs. combined (0.125-8 μg/ml 0.016–2 μg/ml); MIC of voriconazole single vs. combined (0.5–8 μg/ml 0.125–1 μg/ml) | 10 | 42 |
| Co-delivery of anidulafungin with voriconazole demonstrated synergy against 5 Candida auris strains and partial synergy against 22 strains. Co-delivery of anidulafungin with isavuconazole demonstrated synergy against 11 Candida auris strains and partial synergy against 19 strains | 36 | 46 | |||
| Antifungal combinations: 5-fluorocytosine with azoles | 5-fluorocytosine inhibits RNA and DNA synthesis by incorporating 5-fluorouracil into fungal RNA. | Improved MIC when 5-fluorocytosine 1 μg/ml combined with voriconazole (>2 μg/ml vs. 0.015 μg/ml) | 13 | 44 | |
| In the presence of 0.91 μM flucytosine, the IC50 value for voriconazole decreased from 7.2 to 2.9 μM. In the presence of 0.55 μM flucytosine, IC50 value of posaconazole decreased from 0.45 to 0.15 μM. | 1 | 45 | |||
| Antifungal combinations: 5-fluorocytosine with echinocandins | Improved MIC when 5-fluorocytosine 1 μg/ml combined with anidulafungin (4 μg/ml vs. 0.0078 μg/ml) caspofungin (2 μg/ml vs. 0.0078 μg/ml) or micafungin (4 μg/ml vs. 0.0078 μg/ml) | 6 | 44 | ||
| Antifungal combinations: 5-fluorocytosine with polyenes | Polyenes: bind to ergosterol in cell membrane leading to pore formation and leakage of cellular cations and anions, and fungal cell death | Improved MIC when 5-fluorocytosine 1 μg/ml combined with amphotericin B (≥2 μg/ml vs. 0.25 μg/ml) | 9 | 44 | |
| Antifungal and antibiotic combinations: azoles with sulfonamides | Sulfamethoxazole inhibits bacterial folate synthesis leading to the inhibition of bacterial purines and DNA synthesis. The mechanism behind its synergy with azoles is not known. | Co-delivery of fluconazole with sulfamethoxazole demonstrated synergy against 1 Candida auris strain (fluconazole MIC 16 μg/ml vs. 4 μg/ml, sulfamethoxazole MIC 512 μg/ml vs. 16 μg/ml) Co-delivery of voriconazole with sulfamethoxazole demonstrated synergy against 3 Candida auris strain (voriconazole MIC 1–8 μg/ml vs. 0.06–2 μg/ml, sulfamethoxazole MIC 512 μg/ml vs. 16–128 μg/ml Co-delivery of itraconazole with sulfamethoxazole demonstrated synergy against 3 Candida auris strain (itraconazole MIC 1–2 μg/ml vs. 0.25–0.31 μg/ml, sulfamethoxazole MIC 512 μg/ml vs. 16-32 μg/ml) | 3 | 47 | |
| Antifungal and antibiotic combinations: azoles with colistin | Colistin affects the bacterial cytoplasmic membrane, changing its permeability and disrupting the cell membrane. The mechanism behind its synergy with azoles is not known. | Co-delivery of isavuconazole and colistin exhibited synergy against Candida auris (isavuconazole MIC 0.004–0.5 μg/ml vs. 0.001–0.25 μg/ml, colistin MIC 128 μg/ml vs. 8–32 μg/ml) | 15 | 50 | |
| Antifungal and non-antimicrobial drug combinations: azoles with pitavastatin | Pitavastatin competitively inhibit HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase, that catalyses the conversion of HMG-CoA to mevalonate, to inhibit cholesterol biosynthesis. The mechanism behind its synergy with azoles is not known. | Co-delivery of fluconazole and pitavastatin exhibited synergy against Candida auris (fluconazole MIC 256 μg/ml vs. 4–16 μg/ml, colistin MIC 64–128 μg/ml vs. 8–32 μg/ml | 5 | 51 | |
| Antifungal and non-antimicrobial drug combinations: azoles with ospemifene | Ospemifene is a selective estrogen receptor modulator that selectively binds to estrogen receptors to stimulate/inhibit the activity of estrogen in humans. Increased activity of itraconazole is likely to be associated with the increased affinity of ospemifene to multidrug efflux pumps | Co-delivery of itraconazole and ospemifene exhibited synergy against Candida auris (itraconazole MIC 0.5-1 μg/ml vs. 0.125–0.25 μg/ml, ospemifene MIC 256 μg/ml vs. 4 μg/ml | 5 | 53 | |
| Antifungal and non-antimicrobial drug combinations: azoles with aprepitant | Aprepitant is an antiemetic that antagonise substance P/neurokinin 1 (NK1) receptors in humans. Azoles with aprepitant combination may affect C. auris membrane transport processes, ions homeostasis and subsequent ROS detoxifying mechanisms and ergosterol biosynthesis, and fungal glucose transport. | Co-delivery of aprepitant with fluconazole (n = 4), itraconazole (n = 8) or voriconazole (n = 2) exhibited synergy against Candida auris (fluconazole MIC 1–256 μg/ml vs. 0.5–8 μg/ml, itraconazole MIC 0.125–1 μg/ml vs. 0.0312–0.125 μg/ml, voriconazole MIC 0.0078–4 μg/ml vs. 0.062 μg/ml aprepitant MIC > 128 μg/ml vs. 0.5–8 μg/ml) | 10 | 52 | |
| Antifungal and non-antimicrobial drug combinations: azoles with lopinavir | Lopinavir inhibits the activity of HIV-1 protease enzyme that is critical for the HIV viral lifecycle. Azoles with lopinavir combination may affect C. auris membrane transport processes, ions homeostasis and subsequent ROS detoxifying mechanisms and ergosterol biosynthesis, and fungal glucose transport. | Co-delivery of lopinavir with fluconazole (n = 3), itraconazole (n = 10) or voriconazole (n = 6) exhibited synergy against Candida auris (fluconazole MIC 1–256 μg/ml vs. 0.25–32 μg/ml, itraconazole MIC 0.125–1 μg/ml vs. 0.00098–0.0078 μg/ml, voriconazole MIC 0.0078–4 μg/ml vs. 0.0156–0.5 μg/ml lopinavir MIC > 128 μg/ml vs. 1–8 μg/ml) | 10 | 54 | |
| Antifungal and non-antimicrobial compounds combinations: 5-fluorocytosine with myriocin | Myriocin is a serine palmitoyltransferase inhibitor that impede sphingolipid biosynthesis in eukaryotic cells. The mechanism behind its synergy with 5-fluorocytosine is not known. | In the presence of 0.55–0.91 μM flucytosine, the IC50 value for Myriocin decreased from 0.63–2.2 μM to 0.18–0.62 μM. | 3 | 45 | |
| Antifungal and non-antimicrobial compounds combinations: antifungal drugs with Neosartorya fischeri antifungal protein 2; NFAP2 | NFAP2 is a small, cysteine-rich, cationic antifungal protein that is likely to kill Candida spp. via membrane disruption. The mechanism behind its synergy with approved antifungals is not known. | Co-delivery of NFAP2 significantly lowered the MBICs of fluconazole (32- to 128-fold), amphotericin B (4- to 64-fold), anidulafungin (16- to 128-fold), caspofungin (4- to 128-fold), and micafungin (64- to 128-fold). | 5 | 56 | |
| Antifungal and antiseptic combinations: Azoles and domiphen bromide | Domiphen bromide is a cationic surfactant which possibly increases the efficacy of azoles by increasing the permeability of the vacuolar membrane, thereby releasing sequestered azoles. | Co-delivery of to 150 μM of miconazole and 37.5 μM domiphen bromide decreased Candida auris biofilm viability by ∼3 Log10 CFUs | 1 | 57 | |
| Antimicrobial peptides | PepBiotics | Interfere with metabolic activity, fungal growth, and/or viability | Complete suppression activity at <1 μM | 1 | 72 |
| lipopeptide-AF4 | Structural homologue of bacillomycin D which induce ion-conducting pores in the lipid component of the fungal cell membranes and subsequent cell death. | Planktonic MIC: 3.48 μg/ml Biofilm MIC: 2-4 folds of planktonic MIC | 10 | 73 | |
| Cm-p5 | Not known. | MIC 11 μg/ml (free form) MIC < 10 μg/ml in hydrogel form | 1 | 77 | |
| Crotamine | Not known. Functional similarities with human β defensins | MIC50 ∼ 40–160 μM | 5 | 80 | |
| θ defensins | Induce oxidative stress and accumulation of ROS within the fungus. | MICs 3.125–6.25 μg/ml | 2 | 96 | |
| Histatin 5 | Likely to act on multiple intracellular targets leading to nonoxidative events such as intracellular ions leakage, ion imbalance, and volume loss accompanied by vacuolar disruption. | MIC90 7.5 μM | 10 | 97 | |
| Ceragenins (CSA131) | Potentially via membrane perturbation, damage via reactive oxygen species (ROS) and attenuation of mitochondrial functions leading to apoptosis | MIC50 0.5–1 μg/ml MIC90 1 μg/ml MBIC50 2–4 μg/ml MBIC80 4–64 μg/ml | 107 (planktonic) 5 (biofilm) | 99,102,103 | |
| Immunotherapy | Anti-CR3-RP polyclonal antibody | Not known | 1;100 dilution; biofilm formation (36–73% inhibition) and established biofilms (28–46% inhibition) | 3 | 106 |
| Anti-Als3p antibody generated via vaccinating mice with NDV-3A vaccine (based on the N-terminus of Als3 protein) | Enhances macrophage-mediated killing, supresses biofilm formation | Sera from NDV-3A-vaccinated mice (1:10 dilution): 40% increase in macrophage mediated Candida auris killing and 40% survival of mice with Candida auris candidemia | 5 | 107 | |
| Human uterine cervical stem cells conditioned medium (hUCESC-CM) | Not known | Up to 56% of growth suppression | 2 | 108 | |
| Metals and nanoparticles | Gallium | Gallium replaces iron in iron containing proteins to alter the functionality of the protein. This leads to arresting the cellular metabolism and growth | MICs 128–256 μg/ml | 8 | 114 |
| Gold(I)−phosphine complexes | Not fully understood. Gold complexes may inhibit mitochondrial functions of the fungus | MIC of chiral square-planar gold(I) complexes MIC 0.98–7.8 μg/ml and MBIC90 3.9 μg/ml for forming biofilms and 7.8–15.6 μg/ml against preformed biofilms | 2 | 118 | |
| Silver nanoparticles (Completed clinical trial against non-Candida fungal infections) | Exact mechanism is not known. They are likely to attach yeast cell surface, increase the cell wall/membrane permeability, and disrupt the cell membrane integrity, leading to cellular apoptosis. In addition, reduction of cell wall ergosterol and hydrolytic enzyme production in other Candida spp. have been noted | IC50 of 0.06 μg/ml (0.06 ppm) for biofilm formation, and 0.48 μg/ml (0.48 ppm) for preformed biofilms | 1 | 123 | |
| MIC < 0.5–1 μg/ml, MFC 1- ≤ 32 μg/ml IC50 of 0.5–4.9 μg/ml for biofilm formation, and 1.2–6.2 μg/ml for preformed biofilms | 10 | 124 | |||
| Bismuth nanoparticles | Exact mechanism is not known. Likely to alter cell membrane permeability. | MIC 1–4 μg/ml; the IC50 for biofilm formation 5.1–113.1 μg/ml | 10 | 129 | |
| Silver nanoparticles with curcumin | Curcumin is shown to downregulate Δ5,6 desaturase (ERG3) leading to significantly lower ergosterol and accumulation of toxic sterol intermediates which leads to cell death. Also reduces proteinase secretion and alter ATPase activity in fungi. | Silver nanoparticles loaded with curcumin: hydroxypropyl-β-cyclodextrin showed significant reduction of Candida auris in disc diffusion assay | 1 | 134 | |
| Ag-Cu-Co trimetallic nanoparticles | Likely to induce cellular apoptosis and subsequent cell necrosis. Also shown to arrest fungal cell cycle | MIC range of 0.39–0.78 μg/ml | 25 | 131 | |
| 10 mg/ml nanoparticles treatment reduced planktonic CFU by 1.49–10.2 log10 and biofilm CFU by 0.98–9.68 log10 | 6 | 138 | |||
| Miscellaneous drugs/compounds | Phenylthiazole compounds | Not known | Planktonic MIC 2 μg/ml >90% reduction in biofilm formation at 2 μg/ml and >50% reduction in preformed biofilms at 8 μg/ml | 8 | 140 |
| Oxadiazolylthiazoles | Not known | Planktonic MIC 2–4 μg/ml | 3 | 141 | |
| MYC-053 | Inhibits chitin synthesis by blocking chitin synthase, leading to defective fungal cell wall and inhibits nucleic acid synthesis in fungi. | IC50 1–4 μg/ml MIC 4 μg/ml | 5 | 142 | |
| VT-1598 (Completed clinical trial against non-Candida fungal infections) | Inhibits the production of ergosterol by acting on the fungal Cyp51 enzyme. | MIC range 0.03–8 μg/ml (MIC50 0.25 μg/ml and MIC90 1 μg/ml) When treated with up to 50 mg/kg, a longer survival rates (>21 days) and lower fungal burdens in the kidneys of neutropenic murine model infected with Candida auris (mean log10 CFU/g, treated vs. control: 3.67 vs7.26) | 100 | 146 | |
| Arylamidine T-2307 | Trigger mitochondrial membrane collapse in fungi. | MIC50 0.008 to 0.015 μg/ml, and 100% inhibition at 0.25 to >4 μg/ml. Significant reductions in kidney CFU in mice treated at 3 mg/kg (mean 5.06 log10 CFU/g) | 23 | 149 | |
| Drimenol | Likely to affect fungal protein secretion, vacuolar functions, chromatin remodelling and cyclin dependent protein kinase (CDK)-associated functions. | MIC 30 μg/ml; complete inhibition MIC 50 μg/ml | 1 | 151 | |
| Cuminaldehyde derivative | Not known. | MIC50 2–15 μg/ml | 1 | 154 | |
| Amidinourease compounds | Not fully understood; may involve in its uptake and intracellular accumulation within the fungus. | MIC 8–64 μg/ml MBIC 128–256 μg/ml | 18 | 155 | |
| Aryl- and heteroaryl-substituted hydrazones | Not fully understood. Likely to interfere with fungal DNA-protein interactions. | MIC 0.015–7.8 μg/ml; significant suppression of biofilm formation at 15.6–31.3 μg/ml | 10 | 156 | |
| Acetohydroxyacid synthase inhibitors | Blocks the acetohydroxyacid synthase leading to the inhibition of branched-chain amino acid biosynthesis pathway. | MIC50 of bensulfuron methyl 0.09 μM MBIC50 of bensulfuron methyl and chlorimuron ethyl 0.596–1.98 μM | 2 | 158 | |
| Natural compounds | Quorum sensing molecules: farnesol | Farnesol is actively involved in ergosterol biosynthesis, induce intracellular ROS, and disrupt mitochondrial functions in several Candida species. The mechanism of anti-C. auris activity is not yet known. May be associated with reduced activity of drug efflux pumps and downregulation of the genes coding for them | Significant reduction of growth rate for up to 12 h when exposed to 50–300 μM. Co-delivery of farnesol with fluconazole (fluconazole MIC50 > 512 μg/ml vs. 64 μg/ml, Farnesol MIC50 300 μM vs. 75 μM), itraconazole (itraconazole MIC50 8–32 μg/ml vs. 0.5 μg/ml, Farnesol MIC50 300 μM vs. 4.69–9.38 μM), voriconazole (voriconazole MIC50 64 μg/ml vs. 0.5 μg/ml, Farnesol MIC50 150–300 μM vs. 4.69–9.38 μM), posaconazole (posaconazole MIC50 16 μg/ml vs. 0.25 μg/ml, Farnesol MIC50 150 μM vs. 2.34 μM) or isavuconazole (isavuconazole MIC50 4–8 μg/ml vs. 0.125 μg/ml, Farnesol MIC50 300 μM vs. 9.38–18.75 μM) exhibited synergy against Candida auris biofilms | 3 | 167 |
| Co-delivery of farnesol with anidulafungin (anidulafungin MIC50 > 64 μg/ml vs. 1 μg/ml, Farnesol MIC50 300 μM vs. 75–150 μM), caspofungin (caspofungin MIC50 8→64 μg/ml vs. 1 μg/ml, Farnesol MIC50 300 μM vs. 9.38–75 μM), or micafungin (micafungin MIC50 > 64 μg/ml vs. 1 μg/ml, Farnesol MIC50 150–300 μM vs. 37.5–75 μM) exhibited synergy against Candida auris biofilms | 4 | 168 | |||
| MIC of farnesol 62.5–125 mM. Farnesol concentrations of 125 mM inhibited Candida auris adhesion, 7.81 mM inhibited >50% of forming biofilms, and 500 mM inhibited 12 h and 24 h biofilms | 25 | 169 | |||
| Chitosan | Not known; may be associated with direct interactions of chitosan with cell surface leading to cell death | Fungicidal concentration for planktonic cells 5–20 μg/ml; biofilm MIC50 10–80 μg/ml and MIC80 40–160 μg/ml | 4 | 23 | |
| Planktonic MIC 5–20 μg/ml biofilm MIC50 10–80 μg/ml and MIC80 40–160 μg/ml. 200 mg of chitosan/kg of body weight increased the survival rate of Galleria mellonella wax warm infected with Candida auris up to 84% | 8 | 172 | |||
| Plant products: Herbal monomers | Not known; likely to be associated with either the cell wall development mechanics and/or the fungal stress response | Planktonic MICs of 64 μg/ml for sodium houttuyfonate, and 50 μg/ml for cinnamaldehyde, 256 μg/ml for berberine, jatrorrhizine, and palmatine | 1 | 179 | |
| Plant products: trans-cinnamaldehyde | Likely to compromise cell membrane and wall integrity | MIC and MFC 0.03% (v/v) | 1 | 182 | |
| Plant products: α-Cyperone | Not known | Growth inhibition at 150 μg/ml | 1 | 184 | |
| Plant products: 6-Shogaol | Not fully understood; likely to act on drug efflux machinery of the fungus | Planktonic MIC50 16–32 μg/ml and MIC80 32–64 μg/ml. >97% of inhibition of forming and preformed biofilms at 64 μg/ml | 5 | 185 | |
| Bee honey | Specific mechanism is not known; antimicrobial activity of honey is associated with its osmotic activity, low pH, the formation of H2O2, and the presence of various phytochemicals. | 40% honey exposure for 24 h reduced Candida auris growth by 2 Log10 | 32 | 189 | |
| Probiotics (Several completed clinical trials against non-auris Candida infections) | Not known; likely to be associated with secondary metabolite(s) produced by the probiotic yeasts that interfere the pathogen's life cycle; secreted probiotic short-chain fatty acids or bacteriocins or competitive inhibition of the pathogen during attachment. | Significant inhibition of Candida auris (up to 6 log10 CFU) when co-cultured with Lactobacillus paracasei 28.4 or exposed to crude extracts of the lactobacilli supernatant (>15 mg/ml) and its first fraction (3.75– >7.5 mg/ml) | 10 | 192 | |
| Co-inoculation of Candida auris strains with Saccharomyces cerevisiae and Issatchenkia occidentali resulted a 44–62% reduction in C. auris adhesion | 5 | 193 | |||
| Novel antifungal compounds | Ibrexafungerp (SCY-078) (Phase 3 clinical trial; ClinicalTrials.gov Identifier: NCT03363841) | A triterpene glucan synthase inhibitor that inhibits the synthesis of β-1,3-glucan synthase leading to defective cell wall. | MIC 0.0625–2 μg/ml (mode MIC50 0.5 μg/ml and MIC90 1 μg/ml) | 100 | 196 |
| MIC 0.06–8 μg/ml (mode MIC50 0.5 μg/ml) | 200 | 197 | |||
| MIC90 1 μg/ml; significant reduction of the viability and thickness of biofilms when exposed to 4 μg/ml of ibrexafungerp | 16 | 198 | |||
| modal MIC and MIC50 of 0.5 μg/ml (a range of 0.06–2 μg/ml) | 122 | 200 | |||
| SCY-247 | Analog of SCY-078 that inhibits the synthesis of β-1,3-glucan synthase leading to defective cell wall | MIC range 0.06–1 μg/ml (MIC50 and MIC90 0.5 μg/ml). MFC range 0.5–8 μg/ml (MFC50 and MFC90 of 4 μg/ml) | 44 | 204 | |
| Fosmanogepix (APX001/APX001A) (Phase 2 clinical trial; ClinicalTrials.gov Identifier: NCT04148287) | Targets a highly conserved fungal enzyme Gwt1 that catalyses the inositol acylation step of glycosylphosphatidylinositol (GPI) anchored cell wall mannoproteins synthesis. This in turn affects maturation and localization of fungal cell wall mannoproteins, leading to compromised cell wall integrity, defective filamentation and biofilm formation, and severe defects in fungal growth. | MIC50 0.004 μg/ml and MIC90 0.031 μg/ml the exposure of APX001 significantly increased the 16-day survival rate of Candida auris infected immunocompromised mice. | 16 | 208 | |
| MIC50 range < 0.005–0.015 μg/ml (overall modal MIC 0.005 μg/ml, MIC50 0.002 μg/ml and MIC90 0.008 μg/ml) | 100 | 209 | |||
| MIC50 range 0.001–0.125 μg/ml (MIC50 0.016 μg/ml and MIC90 0.03 μg/ml) | 122 | 210 | |||
| Rezafungin (CD101) (Currently on clinical trials against invasive candidiasis; Causative organism unspecified. | Similar to echinocandins | MIC range 0.03–8 μg/ml (mode MIC50 0.125 μg/ml, MIC90 0.5 μg/ml) | 100 | 218 | |
| MIC range 0.06–16 μg/ml (MIC50 0.25 μg/ml, MIC90 1 μg/ml) | 122 | 220 | |||
| Significant reduction of Candida auris in kidney tissues of mice with disseminated Candida auris candidiasis when treated with rezafungin 20 mg/kg intraperitoneally at Day 0, 3 and 6. intravenously administration of rezafungin 400 mg/once a week would likely to meet or exceed the pharmacodynamics target for >90% of C. auris isolates | 4 | 222,223 | |||
| PC945 (Currently on clinical trials against Candida lung infections; Causative organism unspecified.) | Acts on ergosterol synthesis pathway by inhibiting lanosterol 14a-demethylase enzyme coded by ERG11. | MIC50 0.063 μg/ml and MIC90 0.25 μg/ml | 72 | 224 | |
| Ebselen | Not fully understood. It is considered an antioxidant that mimic glutathione peroxidase activity and catalyse the reduction of ROS, leading to the attenuation of damage caused by oxidants and radicals. | Planktonic IC50 0.2345–1.47 μg/ml, complete inhibition at 2.5 μM Biofilm IC50 5.864–9.781 μg/ml | 10 | 225 | |
| Suloctidil | Not fully understood. It may act as an inhibitor of thromboxane synthase or as a thromboxane receptor antagonist. | 16 μg/ml inhibited Candida auris growth by >78% (MIC50 4–8 μg/ml, MIC90 4–16 μg/ml) | 7 | 230 | |
| miltefosine | Not known. Miltefosine is an alkylphosphocholine drug originally developed as an anti-cancer drug. It may inhibit cytochrome-c oxidase within mitochondria leading to mitochondrial dysfunction and apoptosis-like cell death. | Complete elimination of planktonic growth and biofilms formation at 4 μg/ml. a 90% reduction of viability of preformed biofilms at 16 μg/ml. IC50 for Planktonic phase 0.9237–2.472 μg/ml, biofilm formation 1.158–6.049 μg/ml, preformed biofilms 9.144–20.98 μg/ml | 10 | 231 | |
| Iodoquinol | Not known | Complete elimination of planktonic growth at 4 μg/ml IC50 for Planktonic phase 0.2972–2.006 μg/ml, biofilm formation 9.159–56.02 μg/ml, preformed biofilms 38.58- >64 μg/ml | 10 | 231 | |
| Niclosamide and halogenated salicylanilide | An Anthelmintic drug. They are likely to interfere morphological transition and mitochondrial protein import machinery. | Both compounds inhibited Candida auris biofilms at 1 μM | 1 | 233 | |
| Repurposed drugs | Disulfiram | Disulfiram blocks the oxidation of alcohol by irreversibly inactivation aldehyde dehydrogenase in human cells. This results in an accumulation of acetaldehyde in the blood causing highly unpleasant symptoms. Mechanism of antifungal effect is not known. | MIC50 1 μg/ml, MIC80 4–8 μg/ml MBIC80 64–128 μg/ml | 2 | 234 |
| Sertraline (Currently on clinical trials against non-Candida infections) | Sertraline is likely to elicit its effect of C. auris by binding to the Erg11p in the ergosterol biosynthesis pathway. | MIC 20–40 μg/ml; a 71% inhibition of biofilm formation at 20 μg/ml | 3 | 235 | |
| Alexidine dihydrochloride | Targets PTPMT, a mitochondrial tyrosine phosphatase in mammalian cells to drive mitochondrial apoptosis. Mechanism of antifungal effect is not known. | MIC50 0.73–1.5 μg/ml, MIC80 1.5 μg/ml Biofilm formation and mature biofilm inhibition concentrations: MBIC50 and MBIC80 3–6 μg/ml | 2 | 238 | |
| Mefloquine derivatives | Antifungal activity is likely to be due to the disruption of the mitochondrial membrane, interference with mitochondrial DNA stability and disruption vacuoles. | Planktonic MIC 2–8 μg/ml Planktonic MIC against fluconazole resistant isolates 4–16 μg/ml | 5 | 242 |
| Therapeutic group . | Anti-C. auris agent . | Mode of action . | Efficacy . | Number of isolates tested . | Reference . |
|---|---|---|---|---|---|
| Antimicrobial combination therapy | Antifungal combinations: echinocandins with azoles (Ongoing clinical trial against non-Candida fungal infection) | Azoles inhibit 14α-demethylase during ergosterol synthesis to compromise cell membrane integrity and lead to accumulation of toxic sterol intermediates. Echinocandins: inhibit glucan synthesis by supressing beta-1,3-D-glucan synthase leading to a compromised cell wall and subsequent cell lysis | Synergy between micafungin and voriconazole fractional inhibitory concentration index (FICI) <0.5. MIC of micafungin single vs. combined (0.125-8 μg/ml 0.016–2 μg/ml); MIC of voriconazole single vs. combined (0.5–8 μg/ml 0.125–1 μg/ml) | 10 | 42 |
| Co-delivery of anidulafungin with voriconazole demonstrated synergy against 5 Candida auris strains and partial synergy against 22 strains. Co-delivery of anidulafungin with isavuconazole demonstrated synergy against 11 Candida auris strains and partial synergy against 19 strains | 36 | 46 | |||
| Antifungal combinations: 5-fluorocytosine with azoles | 5-fluorocytosine inhibits RNA and DNA synthesis by incorporating 5-fluorouracil into fungal RNA. | Improved MIC when 5-fluorocytosine 1 μg/ml combined with voriconazole (>2 μg/ml vs. 0.015 μg/ml) | 13 | 44 | |
| In the presence of 0.91 μM flucytosine, the IC50 value for voriconazole decreased from 7.2 to 2.9 μM. In the presence of 0.55 μM flucytosine, IC50 value of posaconazole decreased from 0.45 to 0.15 μM. | 1 | 45 | |||
| Antifungal combinations: 5-fluorocytosine with echinocandins | Improved MIC when 5-fluorocytosine 1 μg/ml combined with anidulafungin (4 μg/ml vs. 0.0078 μg/ml) caspofungin (2 μg/ml vs. 0.0078 μg/ml) or micafungin (4 μg/ml vs. 0.0078 μg/ml) | 6 | 44 | ||
| Antifungal combinations: 5-fluorocytosine with polyenes | Polyenes: bind to ergosterol in cell membrane leading to pore formation and leakage of cellular cations and anions, and fungal cell death | Improved MIC when 5-fluorocytosine 1 μg/ml combined with amphotericin B (≥2 μg/ml vs. 0.25 μg/ml) | 9 | 44 | |
| Antifungal and antibiotic combinations: azoles with sulfonamides | Sulfamethoxazole inhibits bacterial folate synthesis leading to the inhibition of bacterial purines and DNA synthesis. The mechanism behind its synergy with azoles is not known. | Co-delivery of fluconazole with sulfamethoxazole demonstrated synergy against 1 Candida auris strain (fluconazole MIC 16 μg/ml vs. 4 μg/ml, sulfamethoxazole MIC 512 μg/ml vs. 16 μg/ml) Co-delivery of voriconazole with sulfamethoxazole demonstrated synergy against 3 Candida auris strain (voriconazole MIC 1–8 μg/ml vs. 0.06–2 μg/ml, sulfamethoxazole MIC 512 μg/ml vs. 16–128 μg/ml Co-delivery of itraconazole with sulfamethoxazole demonstrated synergy against 3 Candida auris strain (itraconazole MIC 1–2 μg/ml vs. 0.25–0.31 μg/ml, sulfamethoxazole MIC 512 μg/ml vs. 16-32 μg/ml) | 3 | 47 | |
| Antifungal and antibiotic combinations: azoles with colistin | Colistin affects the bacterial cytoplasmic membrane, changing its permeability and disrupting the cell membrane. The mechanism behind its synergy with azoles is not known. | Co-delivery of isavuconazole and colistin exhibited synergy against Candida auris (isavuconazole MIC 0.004–0.5 μg/ml vs. 0.001–0.25 μg/ml, colistin MIC 128 μg/ml vs. 8–32 μg/ml) | 15 | 50 | |
| Antifungal and non-antimicrobial drug combinations: azoles with pitavastatin | Pitavastatin competitively inhibit HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase, that catalyses the conversion of HMG-CoA to mevalonate, to inhibit cholesterol biosynthesis. The mechanism behind its synergy with azoles is not known. | Co-delivery of fluconazole and pitavastatin exhibited synergy against Candida auris (fluconazole MIC 256 μg/ml vs. 4–16 μg/ml, colistin MIC 64–128 μg/ml vs. 8–32 μg/ml | 5 | 51 | |
| Antifungal and non-antimicrobial drug combinations: azoles with ospemifene | Ospemifene is a selective estrogen receptor modulator that selectively binds to estrogen receptors to stimulate/inhibit the activity of estrogen in humans. Increased activity of itraconazole is likely to be associated with the increased affinity of ospemifene to multidrug efflux pumps | Co-delivery of itraconazole and ospemifene exhibited synergy against Candida auris (itraconazole MIC 0.5-1 μg/ml vs. 0.125–0.25 μg/ml, ospemifene MIC 256 μg/ml vs. 4 μg/ml | 5 | 53 | |
| Antifungal and non-antimicrobial drug combinations: azoles with aprepitant | Aprepitant is an antiemetic that antagonise substance P/neurokinin 1 (NK1) receptors in humans. Azoles with aprepitant combination may affect C. auris membrane transport processes, ions homeostasis and subsequent ROS detoxifying mechanisms and ergosterol biosynthesis, and fungal glucose transport. | Co-delivery of aprepitant with fluconazole (n = 4), itraconazole (n = 8) or voriconazole (n = 2) exhibited synergy against Candida auris (fluconazole MIC 1–256 μg/ml vs. 0.5–8 μg/ml, itraconazole MIC 0.125–1 μg/ml vs. 0.0312–0.125 μg/ml, voriconazole MIC 0.0078–4 μg/ml vs. 0.062 μg/ml aprepitant MIC > 128 μg/ml vs. 0.5–8 μg/ml) | 10 | 52 | |
| Antifungal and non-antimicrobial drug combinations: azoles with lopinavir | Lopinavir inhibits the activity of HIV-1 protease enzyme that is critical for the HIV viral lifecycle. Azoles with lopinavir combination may affect C. auris membrane transport processes, ions homeostasis and subsequent ROS detoxifying mechanisms and ergosterol biosynthesis, and fungal glucose transport. | Co-delivery of lopinavir with fluconazole (n = 3), itraconazole (n = 10) or voriconazole (n = 6) exhibited synergy against Candida auris (fluconazole MIC 1–256 μg/ml vs. 0.25–32 μg/ml, itraconazole MIC 0.125–1 μg/ml vs. 0.00098–0.0078 μg/ml, voriconazole MIC 0.0078–4 μg/ml vs. 0.0156–0.5 μg/ml lopinavir MIC > 128 μg/ml vs. 1–8 μg/ml) | 10 | 54 | |
| Antifungal and non-antimicrobial compounds combinations: 5-fluorocytosine with myriocin | Myriocin is a serine palmitoyltransferase inhibitor that impede sphingolipid biosynthesis in eukaryotic cells. The mechanism behind its synergy with 5-fluorocytosine is not known. | In the presence of 0.55–0.91 μM flucytosine, the IC50 value for Myriocin decreased from 0.63–2.2 μM to 0.18–0.62 μM. | 3 | 45 | |
| Antifungal and non-antimicrobial compounds combinations: antifungal drugs with Neosartorya fischeri antifungal protein 2; NFAP2 | NFAP2 is a small, cysteine-rich, cationic antifungal protein that is likely to kill Candida spp. via membrane disruption. The mechanism behind its synergy with approved antifungals is not known. | Co-delivery of NFAP2 significantly lowered the MBICs of fluconazole (32- to 128-fold), amphotericin B (4- to 64-fold), anidulafungin (16- to 128-fold), caspofungin (4- to 128-fold), and micafungin (64- to 128-fold). | 5 | 56 | |
| Antifungal and antiseptic combinations: Azoles and domiphen bromide | Domiphen bromide is a cationic surfactant which possibly increases the efficacy of azoles by increasing the permeability of the vacuolar membrane, thereby releasing sequestered azoles. | Co-delivery of to 150 μM of miconazole and 37.5 μM domiphen bromide decreased Candida auris biofilm viability by ∼3 Log10 CFUs | 1 | 57 | |
| Antimicrobial peptides | PepBiotics | Interfere with metabolic activity, fungal growth, and/or viability | Complete suppression activity at <1 μM | 1 | 72 |
| lipopeptide-AF4 | Structural homologue of bacillomycin D which induce ion-conducting pores in the lipid component of the fungal cell membranes and subsequent cell death. | Planktonic MIC: 3.48 μg/ml Biofilm MIC: 2-4 folds of planktonic MIC | 10 | 73 | |
| Cm-p5 | Not known. | MIC 11 μg/ml (free form) MIC < 10 μg/ml in hydrogel form | 1 | 77 | |
| Crotamine | Not known. Functional similarities with human β defensins | MIC50 ∼ 40–160 μM | 5 | 80 | |
| θ defensins | Induce oxidative stress and accumulation of ROS within the fungus. | MICs 3.125–6.25 μg/ml | 2 | 96 | |
| Histatin 5 | Likely to act on multiple intracellular targets leading to nonoxidative events such as intracellular ions leakage, ion imbalance, and volume loss accompanied by vacuolar disruption. | MIC90 7.5 μM | 10 | 97 | |
| Ceragenins (CSA131) | Potentially via membrane perturbation, damage via reactive oxygen species (ROS) and attenuation of mitochondrial functions leading to apoptosis | MIC50 0.5–1 μg/ml MIC90 1 μg/ml MBIC50 2–4 μg/ml MBIC80 4–64 μg/ml | 107 (planktonic) 5 (biofilm) | 99,102,103 | |
| Immunotherapy | Anti-CR3-RP polyclonal antibody | Not known | 1;100 dilution; biofilm formation (36–73% inhibition) and established biofilms (28–46% inhibition) | 3 | 106 |
| Anti-Als3p antibody generated via vaccinating mice with NDV-3A vaccine (based on the N-terminus of Als3 protein) | Enhances macrophage-mediated killing, supresses biofilm formation | Sera from NDV-3A-vaccinated mice (1:10 dilution): 40% increase in macrophage mediated Candida auris killing and 40% survival of mice with Candida auris candidemia | 5 | 107 | |
| Human uterine cervical stem cells conditioned medium (hUCESC-CM) | Not known | Up to 56% of growth suppression | 2 | 108 | |
| Metals and nanoparticles | Gallium | Gallium replaces iron in iron containing proteins to alter the functionality of the protein. This leads to arresting the cellular metabolism and growth | MICs 128–256 μg/ml | 8 | 114 |
| Gold(I)−phosphine complexes | Not fully understood. Gold complexes may inhibit mitochondrial functions of the fungus | MIC of chiral square-planar gold(I) complexes MIC 0.98–7.8 μg/ml and MBIC90 3.9 μg/ml for forming biofilms and 7.8–15.6 μg/ml against preformed biofilms | 2 | 118 | |
| Silver nanoparticles (Completed clinical trial against non-Candida fungal infections) | Exact mechanism is not known. They are likely to attach yeast cell surface, increase the cell wall/membrane permeability, and disrupt the cell membrane integrity, leading to cellular apoptosis. In addition, reduction of cell wall ergosterol and hydrolytic enzyme production in other Candida spp. have been noted | IC50 of 0.06 μg/ml (0.06 ppm) for biofilm formation, and 0.48 μg/ml (0.48 ppm) for preformed biofilms | 1 | 123 | |
| MIC < 0.5–1 μg/ml, MFC 1- ≤ 32 μg/ml IC50 of 0.5–4.9 μg/ml for biofilm formation, and 1.2–6.2 μg/ml for preformed biofilms | 10 | 124 | |||
| Bismuth nanoparticles | Exact mechanism is not known. Likely to alter cell membrane permeability. | MIC 1–4 μg/ml; the IC50 for biofilm formation 5.1–113.1 μg/ml | 10 | 129 | |
| Silver nanoparticles with curcumin | Curcumin is shown to downregulate Δ5,6 desaturase (ERG3) leading to significantly lower ergosterol and accumulation of toxic sterol intermediates which leads to cell death. Also reduces proteinase secretion and alter ATPase activity in fungi. | Silver nanoparticles loaded with curcumin: hydroxypropyl-β-cyclodextrin showed significant reduction of Candida auris in disc diffusion assay | 1 | 134 | |
| Ag-Cu-Co trimetallic nanoparticles | Likely to induce cellular apoptosis and subsequent cell necrosis. Also shown to arrest fungal cell cycle | MIC range of 0.39–0.78 μg/ml | 25 | 131 | |
| 10 mg/ml nanoparticles treatment reduced planktonic CFU by 1.49–10.2 log10 and biofilm CFU by 0.98–9.68 log10 | 6 | 138 | |||
| Miscellaneous drugs/compounds | Phenylthiazole compounds | Not known | Planktonic MIC 2 μg/ml >90% reduction in biofilm formation at 2 μg/ml and >50% reduction in preformed biofilms at 8 μg/ml | 8 | 140 |
| Oxadiazolylthiazoles | Not known | Planktonic MIC 2–4 μg/ml | 3 | 141 | |
| MYC-053 | Inhibits chitin synthesis by blocking chitin synthase, leading to defective fungal cell wall and inhibits nucleic acid synthesis in fungi. | IC50 1–4 μg/ml MIC 4 μg/ml | 5 | 142 | |
| VT-1598 (Completed clinical trial against non-Candida fungal infections) | Inhibits the production of ergosterol by acting on the fungal Cyp51 enzyme. | MIC range 0.03–8 μg/ml (MIC50 0.25 μg/ml and MIC90 1 μg/ml) When treated with up to 50 mg/kg, a longer survival rates (>21 days) and lower fungal burdens in the kidneys of neutropenic murine model infected with Candida auris (mean log10 CFU/g, treated vs. control: 3.67 vs7.26) | 100 | 146 | |
| Arylamidine T-2307 | Trigger mitochondrial membrane collapse in fungi. | MIC50 0.008 to 0.015 μg/ml, and 100% inhibition at 0.25 to >4 μg/ml. Significant reductions in kidney CFU in mice treated at 3 mg/kg (mean 5.06 log10 CFU/g) | 23 | 149 | |
| Drimenol | Likely to affect fungal protein secretion, vacuolar functions, chromatin remodelling and cyclin dependent protein kinase (CDK)-associated functions. | MIC 30 μg/ml; complete inhibition MIC 50 μg/ml | 1 | 151 | |
| Cuminaldehyde derivative | Not known. | MIC50 2–15 μg/ml | 1 | 154 | |
| Amidinourease compounds | Not fully understood; may involve in its uptake and intracellular accumulation within the fungus. | MIC 8–64 μg/ml MBIC 128–256 μg/ml | 18 | 155 | |
| Aryl- and heteroaryl-substituted hydrazones | Not fully understood. Likely to interfere with fungal DNA-protein interactions. | MIC 0.015–7.8 μg/ml; significant suppression of biofilm formation at 15.6–31.3 μg/ml | 10 | 156 | |
| Acetohydroxyacid synthase inhibitors | Blocks the acetohydroxyacid synthase leading to the inhibition of branched-chain amino acid biosynthesis pathway. | MIC50 of bensulfuron methyl 0.09 μM MBIC50 of bensulfuron methyl and chlorimuron ethyl 0.596–1.98 μM | 2 | 158 | |
| Natural compounds | Quorum sensing molecules: farnesol | Farnesol is actively involved in ergosterol biosynthesis, induce intracellular ROS, and disrupt mitochondrial functions in several Candida species. The mechanism of anti-C. auris activity is not yet known. May be associated with reduced activity of drug efflux pumps and downregulation of the genes coding for them | Significant reduction of growth rate for up to 12 h when exposed to 50–300 μM. Co-delivery of farnesol with fluconazole (fluconazole MIC50 > 512 μg/ml vs. 64 μg/ml, Farnesol MIC50 300 μM vs. 75 μM), itraconazole (itraconazole MIC50 8–32 μg/ml vs. 0.5 μg/ml, Farnesol MIC50 300 μM vs. 4.69–9.38 μM), voriconazole (voriconazole MIC50 64 μg/ml vs. 0.5 μg/ml, Farnesol MIC50 150–300 μM vs. 4.69–9.38 μM), posaconazole (posaconazole MIC50 16 μg/ml vs. 0.25 μg/ml, Farnesol MIC50 150 μM vs. 2.34 μM) or isavuconazole (isavuconazole MIC50 4–8 μg/ml vs. 0.125 μg/ml, Farnesol MIC50 300 μM vs. 9.38–18.75 μM) exhibited synergy against Candida auris biofilms | 3 | 167 |
| Co-delivery of farnesol with anidulafungin (anidulafungin MIC50 > 64 μg/ml vs. 1 μg/ml, Farnesol MIC50 300 μM vs. 75–150 μM), caspofungin (caspofungin MIC50 8→64 μg/ml vs. 1 μg/ml, Farnesol MIC50 300 μM vs. 9.38–75 μM), or micafungin (micafungin MIC50 > 64 μg/ml vs. 1 μg/ml, Farnesol MIC50 150–300 μM vs. 37.5–75 μM) exhibited synergy against Candida auris biofilms | 4 | 168 | |||
| MIC of farnesol 62.5–125 mM. Farnesol concentrations of 125 mM inhibited Candida auris adhesion, 7.81 mM inhibited >50% of forming biofilms, and 500 mM inhibited 12 h and 24 h biofilms | 25 | 169 | |||
| Chitosan | Not known; may be associated with direct interactions of chitosan with cell surface leading to cell death | Fungicidal concentration for planktonic cells 5–20 μg/ml; biofilm MIC50 10–80 μg/ml and MIC80 40–160 μg/ml | 4 | 23 | |
| Planktonic MIC 5–20 μg/ml biofilm MIC50 10–80 μg/ml and MIC80 40–160 μg/ml. 200 mg of chitosan/kg of body weight increased the survival rate of Galleria mellonella wax warm infected with Candida auris up to 84% | 8 | 172 | |||
| Plant products: Herbal monomers | Not known; likely to be associated with either the cell wall development mechanics and/or the fungal stress response | Planktonic MICs of 64 μg/ml for sodium houttuyfonate, and 50 μg/ml for cinnamaldehyde, 256 μg/ml for berberine, jatrorrhizine, and palmatine | 1 | 179 | |
| Plant products: trans-cinnamaldehyde | Likely to compromise cell membrane and wall integrity | MIC and MFC 0.03% (v/v) | 1 | 182 | |
| Plant products: α-Cyperone | Not known | Growth inhibition at 150 μg/ml | 1 | 184 | |
| Plant products: 6-Shogaol | Not fully understood; likely to act on drug efflux machinery of the fungus | Planktonic MIC50 16–32 μg/ml and MIC80 32–64 μg/ml. >97% of inhibition of forming and preformed biofilms at 64 μg/ml | 5 | 185 | |
| Bee honey | Specific mechanism is not known; antimicrobial activity of honey is associated with its osmotic activity, low pH, the formation of H2O2, and the presence of various phytochemicals. | 40% honey exposure for 24 h reduced Candida auris growth by 2 Log10 | 32 | 189 | |
| Probiotics (Several completed clinical trials against non-auris Candida infections) | Not known; likely to be associated with secondary metabolite(s) produced by the probiotic yeasts that interfere the pathogen's life cycle; secreted probiotic short-chain fatty acids or bacteriocins or competitive inhibition of the pathogen during attachment. | Significant inhibition of Candida auris (up to 6 log10 CFU) when co-cultured with Lactobacillus paracasei 28.4 or exposed to crude extracts of the lactobacilli supernatant (>15 mg/ml) and its first fraction (3.75– >7.5 mg/ml) | 10 | 192 | |
| Co-inoculation of Candida auris strains with Saccharomyces cerevisiae and Issatchenkia occidentali resulted a 44–62% reduction in C. auris adhesion | 5 | 193 | |||
| Novel antifungal compounds | Ibrexafungerp (SCY-078) (Phase 3 clinical trial; ClinicalTrials.gov Identifier: NCT03363841) | A triterpene glucan synthase inhibitor that inhibits the synthesis of β-1,3-glucan synthase leading to defective cell wall. | MIC 0.0625–2 μg/ml (mode MIC50 0.5 μg/ml and MIC90 1 μg/ml) | 100 | 196 |
| MIC 0.06–8 μg/ml (mode MIC50 0.5 μg/ml) | 200 | 197 | |||
| MIC90 1 μg/ml; significant reduction of the viability and thickness of biofilms when exposed to 4 μg/ml of ibrexafungerp | 16 | 198 | |||
| modal MIC and MIC50 of 0.5 μg/ml (a range of 0.06–2 μg/ml) | 122 | 200 | |||
| SCY-247 | Analog of SCY-078 that inhibits the synthesis of β-1,3-glucan synthase leading to defective cell wall | MIC range 0.06–1 μg/ml (MIC50 and MIC90 0.5 μg/ml). MFC range 0.5–8 μg/ml (MFC50 and MFC90 of 4 μg/ml) | 44 | 204 | |
| Fosmanogepix (APX001/APX001A) (Phase 2 clinical trial; ClinicalTrials.gov Identifier: NCT04148287) | Targets a highly conserved fungal enzyme Gwt1 that catalyses the inositol acylation step of glycosylphosphatidylinositol (GPI) anchored cell wall mannoproteins synthesis. This in turn affects maturation and localization of fungal cell wall mannoproteins, leading to compromised cell wall integrity, defective filamentation and biofilm formation, and severe defects in fungal growth. | MIC50 0.004 μg/ml and MIC90 0.031 μg/ml the exposure of APX001 significantly increased the 16-day survival rate of Candida auris infected immunocompromised mice. | 16 | 208 | |
| MIC50 range < 0.005–0.015 μg/ml (overall modal MIC 0.005 μg/ml, MIC50 0.002 μg/ml and MIC90 0.008 μg/ml) | 100 | 209 | |||
| MIC50 range 0.001–0.125 μg/ml (MIC50 0.016 μg/ml and MIC90 0.03 μg/ml) | 122 | 210 | |||
| Rezafungin (CD101) (Currently on clinical trials against invasive candidiasis; Causative organism unspecified. | Similar to echinocandins | MIC range 0.03–8 μg/ml (mode MIC50 0.125 μg/ml, MIC90 0.5 μg/ml) | 100 | 218 | |
| MIC range 0.06–16 μg/ml (MIC50 0.25 μg/ml, MIC90 1 μg/ml) | 122 | 220 | |||
| Significant reduction of Candida auris in kidney tissues of mice with disseminated Candida auris candidiasis when treated with rezafungin 20 mg/kg intraperitoneally at Day 0, 3 and 6. intravenously administration of rezafungin 400 mg/once a week would likely to meet or exceed the pharmacodynamics target for >90% of C. auris isolates | 4 | 222,223 | |||
| PC945 (Currently on clinical trials against Candida lung infections; Causative organism unspecified.) | Acts on ergosterol synthesis pathway by inhibiting lanosterol 14a-demethylase enzyme coded by ERG11. | MIC50 0.063 μg/ml and MIC90 0.25 μg/ml | 72 | 224 | |
| Ebselen | Not fully understood. It is considered an antioxidant that mimic glutathione peroxidase activity and catalyse the reduction of ROS, leading to the attenuation of damage caused by oxidants and radicals. | Planktonic IC50 0.2345–1.47 μg/ml, complete inhibition at 2.5 μM Biofilm IC50 5.864–9.781 μg/ml | 10 | 225 | |
| Suloctidil | Not fully understood. It may act as an inhibitor of thromboxane synthase or as a thromboxane receptor antagonist. | 16 μg/ml inhibited Candida auris growth by >78% (MIC50 4–8 μg/ml, MIC90 4–16 μg/ml) | 7 | 230 | |
| miltefosine | Not known. Miltefosine is an alkylphosphocholine drug originally developed as an anti-cancer drug. It may inhibit cytochrome-c oxidase within mitochondria leading to mitochondrial dysfunction and apoptosis-like cell death. | Complete elimination of planktonic growth and biofilms formation at 4 μg/ml. a 90% reduction of viability of preformed biofilms at 16 μg/ml. IC50 for Planktonic phase 0.9237–2.472 μg/ml, biofilm formation 1.158–6.049 μg/ml, preformed biofilms 9.144–20.98 μg/ml | 10 | 231 | |
| Iodoquinol | Not known | Complete elimination of planktonic growth at 4 μg/ml IC50 for Planktonic phase 0.2972–2.006 μg/ml, biofilm formation 9.159–56.02 μg/ml, preformed biofilms 38.58- >64 μg/ml | 10 | 231 | |
| Niclosamide and halogenated salicylanilide | An Anthelmintic drug. They are likely to interfere morphological transition and mitochondrial protein import machinery. | Both compounds inhibited Candida auris biofilms at 1 μM | 1 | 233 | |
| Repurposed drugs | Disulfiram | Disulfiram blocks the oxidation of alcohol by irreversibly inactivation aldehyde dehydrogenase in human cells. This results in an accumulation of acetaldehyde in the blood causing highly unpleasant symptoms. Mechanism of antifungal effect is not known. | MIC50 1 μg/ml, MIC80 4–8 μg/ml MBIC80 64–128 μg/ml | 2 | 234 |
| Sertraline (Currently on clinical trials against non-Candida infections) | Sertraline is likely to elicit its effect of C. auris by binding to the Erg11p in the ergosterol biosynthesis pathway. | MIC 20–40 μg/ml; a 71% inhibition of biofilm formation at 20 μg/ml | 3 | 235 | |
| Alexidine dihydrochloride | Targets PTPMT, a mitochondrial tyrosine phosphatase in mammalian cells to drive mitochondrial apoptosis. Mechanism of antifungal effect is not known. | MIC50 0.73–1.5 μg/ml, MIC80 1.5 μg/ml Biofilm formation and mature biofilm inhibition concentrations: MBIC50 and MBIC80 3–6 μg/ml | 2 | 238 | |
| Mefloquine derivatives | Antifungal activity is likely to be due to the disruption of the mitochondrial membrane, interference with mitochondrial DNA stability and disruption vacuoles. | Planktonic MIC 2–8 μg/ml Planktonic MIC against fluconazole resistant isolates 4–16 μg/ml | 5 | 242 |
FICI: Fractional inhibitory concentration index, MIC: Minimum inhibitory concentration, IC50: 50% of maximum inhibitory concentration, ROS: Reactive oxygen species, CFU: Colony forming units, ATP: Adenosine triphosphate, MBIC50: The Minimal Biofilm Inhibition Concentration 50%, MBIC80: The Minimal Biofilm Inhibition Concentration 80%, MBIC90: The Minimal Biofilm Inhibition Concentration 90%, UV-C: Ultraviolet light -C.
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