Table 1. Open in new tab Molecular...

Gene	Gene Function		Mutations Identified in Delamanid-resistant Clinical Isolates
*ddn* (Rv3547)	Prodrug activation of delamanid	Fdn (F420-independent nitroreductase) metabolizes delamanid into its active form	t320c (L107P) (single missense mutation)	1	MDR-TB	2	[5]
			59–101 deletion (14 amino acid deletion)	>8	MDR-TB	2	[5]
			Trp-88→STOP (stop codon mutation)	≥16	MDR-TB	159	[19]
				4 (APM) >2 (REMA)	MDR-TB	19	[20]

			G53D (amino acid substitution)	0.25	XDR-TB	1	[21]
*fgd1* (Rv0407)	Prodrug activation of delamanid	Fgd1 (G6P dehydrogenase) recycles F420 into the reduced form	t960c (synonymous mutation)	>8	MDR-TB	2	[5]
			G49^fs (amino acid deletion)	≥2	XDR-TB	1	[3]
*fbiA* (Rv3261)	F420 synthetic pathway	*FbiA* modifies flavin FO further to F420	Lys-250→STOP (stop codon mutation)	≥16	XDR-TB	159	[19]
			D49Y (single amino acid substitution)	≥2	XDR-TB	1, 1	[3, 17]
*fbiB* (Rv3262)	F420 synthetic pathway	FbiA modifies flavin further to F420	Not yet determined
*fbiC* (Rv1173)	F420 synthetic pathway	catalyzes the synthesis of FO	V318I (single amino acid substitution)	32	XDR-TB	90	[11]
			R536L (Arg536Leu substitution)	0.25 (APM) 2 (REMA)	DR-TB	19	[20]

Gene

Gene Function

Mutations Identified in Delamanid-resistant Clinical Isolates

Mutation Type

Delamanid MIC (mg/L)

Resistance Pattern

Number of Isolates Studied

Reference

ddn (Rv3547)

Prodrug activation of delamanid

Fdn (F420-independent nitroreductase) metabolizes delamanid into its active form

t320c (L107P) (single missense mutation)

MDR-TB

[5]

59–101 deletion (14 amino acid deletion)

MDR-TB

[5]

Trp-88→STOP (stop codon mutation)

≥16

MDR-TB

159

[19]

4 (APM)
>2 (REMA)

MDR-TB

[20]

G53D (amino acid substitution)

0.25

XDR-TB

[21]

fgd1 (Rv0407)

Prodrug activation of delamanid

Fgd1 (G6P dehydrogenase) recycles F420 into the reduced form

t960c (synonymous mutation)

MDR-TB

[5]

G49^fs (amino acid deletion)

≥2

XDR-TB

[3]

fbiA (Rv3261)

F420 synthetic pathway

FbiA modifies flavin FO further to F420

Lys-250→STOP (stop codon mutation)

≥16

XDR-TB

159

[19]

D49Y (single amino acid substitution)

≥2

XDR-TB

1, 1

[3, 17]

fbiB (Rv3262)

F420 synthetic pathway

FbiA modifies flavin further to F420

Not yet determined

fbiC (Rv1173)

F420 synthetic pathway

catalyzes the synthesis of FO

V318I (single amino acid substitution)

XDR-TB

[11]

R536L (Arg536Leu substitution)

0.25 (APM)
2 (REMA)

DR-TB

[20]

Gene	Gene Function		Mutations Identified in Delamanid-resistant Clinical Isolates
*ddn* (Rv3547)	Prodrug activation of delamanid	Fdn (F420-independent nitroreductase) metabolizes delamanid into its active form	t320c (L107P) (single missense mutation)	1	MDR-TB	2	[5]
			59–101 deletion (14 amino acid deletion)	>8	MDR-TB	2	[5]
			Trp-88→STOP (stop codon mutation)	≥16	MDR-TB	159	[19]
				4 (APM) >2 (REMA)	MDR-TB	19	[20]

			G53D (amino acid substitution)	0.25	XDR-TB	1	[21]
*fgd1* (Rv0407)	Prodrug activation of delamanid	Fgd1 (G6P dehydrogenase) recycles F420 into the reduced form	t960c (synonymous mutation)	>8	MDR-TB	2	[5]
			G49^fs (amino acid deletion)	≥2	XDR-TB	1	[3]
*fbiA* (Rv3261)	F420 synthetic pathway	*FbiA* modifies flavin FO further to F420	Lys-250→STOP (stop codon mutation)	≥16	XDR-TB	159	[19]
			D49Y (single amino acid substitution)	≥2	XDR-TB	1, 1	[3, 17]
*fbiB* (Rv3262)	F420 synthetic pathway	FbiA modifies flavin further to F420	Not yet determined
*fbiC* (Rv1173)	F420 synthetic pathway	catalyzes the synthesis of FO	V318I (single amino acid substitution)	32	XDR-TB	90	[11]
			R536L (Arg536Leu substitution)	0.25 (APM) 2 (REMA)	DR-TB	19	[20]

Table 1.

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Molecular Mechanisms of Delamanid Resistance

Gene	Gene Function		Mutations Identified in Delamanid-resistant Clinical Isolates
			Mutation Type	Delamanid MIC (mg/L)	Resistance Pattern	Number of Isolates Studied	Reference
*ddn* (Rv3547)	Prodrug activation of delamanid	Fdn (F420-independent nitroreductase) metabolizes delamanid into its active form	t320c (L107P) (single missense mutation)	1	MDR-TB	2	[5]
			59–101 deletion (14 amino acid deletion)	>8	MDR-TB	2	[5]
			Trp-88→STOP (stop codon mutation)	≥16	MDR-TB	159	[19]
				4 (APM) >2 (REMA)	MDR-TB	19	[20]

			G53D (amino acid substitution)	0.25	XDR-TB	1	[21]
*fgd1* (Rv0407)	Prodrug activation of delamanid	Fgd1 (G6P dehydrogenase) recycles F420 into the reduced form	t960c (synonymous mutation)	>8	MDR-TB	2	[5]
			G49^fs (amino acid deletion)	≥2	XDR-TB	1	[3]
*fbiA* (Rv3261)	F420 synthetic pathway	*FbiA* modifies flavin FO further to F420	Lys-250→STOP (stop codon mutation)	≥16	XDR-TB	159	[19]
			D49Y (single amino acid substitution)	≥2	XDR-TB	1, 1	[3, 17]
*fbiB* (Rv3262)	F420 synthetic pathway	FbiA modifies flavin further to F420	Not yet determined
*fbiC* (Rv1173)	F420 synthetic pathway	catalyzes the synthesis of FO	V318I (single amino acid substitution)	32	XDR-TB	90	[11]
			R536L (Arg536Leu substitution)	0.25 (APM) 2 (REMA)	DR-TB	19	[20]

Gene	Gene Function		Mutations Identified in Delamanid-resistant Clinical Isolates
			Mutation Type	Delamanid MIC (mg/L)	Resistance Pattern	Number of Isolates Studied	Reference
*ddn* (Rv3547)	Prodrug activation of delamanid	Fdn (F420-independent nitroreductase) metabolizes delamanid into its active form	t320c (L107P) (single missense mutation)	1	MDR-TB	2	[5]
			59–101 deletion (14 amino acid deletion)	>8	MDR-TB	2	[5]
			Trp-88→STOP (stop codon mutation)	≥16	MDR-TB	159	[19]
				4 (APM) >2 (REMA)	MDR-TB	19	[20]

			G53D (amino acid substitution)	0.25	XDR-TB	1	[21]
*fgd1* (Rv0407)	Prodrug activation of delamanid	Fgd1 (G6P dehydrogenase) recycles F420 into the reduced form	t960c (synonymous mutation)	>8	MDR-TB	2	[5]
			G49^fs (amino acid deletion)	≥2	XDR-TB	1	[3]
*fbiA* (Rv3261)	F420 synthetic pathway	*FbiA* modifies flavin FO further to F420	Lys-250→STOP (stop codon mutation)	≥16	XDR-TB	159	[19]
			D49Y (single amino acid substitution)	≥2	XDR-TB	1, 1	[3, 17]
*fbiB* (Rv3262)	F420 synthetic pathway	FbiA modifies flavin further to F420	Not yet determined
*fbiC* (Rv1173)	F420 synthetic pathway	catalyzes the synthesis of FO	V318I (single amino acid substitution)	32	XDR-TB	90	[11]
			R536L (Arg536Leu substitution)	0.25 (APM) 2 (REMA)	DR-TB	19	[20]

Abbreviations: APM, agar proportion method; DR-TB, drug-resistant tuberculosis; MDR-TB, multidrug-resistant tuberculosis; REMA, resazurin microtiter assay; XDR-TB, extensively drug-resistant tuberculosis.

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