Deciphering drug resistance in Mycobacterium tuberculosis using whole-genome sequencing: progress, promise, and challenges

Cohen, Keira A.; Manson, Abigail L.; Desjardins, Christopher A.; Abeel, Thomas; Earl, Ashlee M.

doi:10.1186/s13073-019-0660-8

Table 1 Antitubercular drug-resistance mechanisms^a

From: Deciphering drug resistance in Mycobacterium tuberculosis using whole-genome sequencing: progress, promise, and challenges

WHO category	Drug or drug class	Resistance genes	Rv number	Gene function	Mechanism of drug resistance	Reference(s)
First-line agents	Rifamycins (for example, rifampicin)	rpoB	Rv0667	RNA polymerase	Target modification	[6]
	Rifamycins (for example, rifampicin)	ponA1	Rv0050	Probable bifunctional penicillin-binding protein	Unknown	[7]
	Isoniazid	katG	Rv1908c	Catalase-peroxidase enzyme	Decreased drug activation	[8]
	Isoniazid	inhA	Rv1484	NADH-dependent enoyl-acyl carrier protein	Target amplification or modification	[9, 10]
	Pyrazinamide^b	pncA	Rv2043c	Pyrazinamidase	Decreased drug activation	[11, 12]
		panD	Rv3601c	Aspartate decarboxylase	Unknown	[13]
		rpsA	RRv1630	Ribosomal protein S1	Target modification	[14]
	Ethambutol^b	embCAB operon	Rv3793-5	Arabinosyltransferase	Target modification	[15, 16]
	Ethambutol^b	ubiA	Rv3806c	Arabinogalactan synthesis	Gain-of-function	[15]
Group A	Levofloxacin Moxifloxacin	gyrA	Rv0006	DNA gyrase A	Target modification	[17, 18]
	Levofloxacin Moxifloxacin	gyrB	Rv0005	DNA gyrase B	Target modification	[18]
	Bedaquiline	atpE	Rv1305	ATP synthase	Target modification	[19]
		pepQ	Rv2535c	Putative Xaa-Pro aminopeptidase	Unknown	[20]
		Rv0678	Rv0678	Transcriptional regulator of mmpL5	Drug efflux	[21, 22]
	Linezolid	Rrl	NA	23S rRNA	Target modification	[23]
	Linezolid	rplC	Rv0701	50S ribosomal protein L3	Target modification	[24]
Group B	Clofazimine	pepQ	Rv2535c	Putative Xaa-Pro aminopeptidase	Drug efflux	[20]
	Clofazimine	Rv0678	Rv0678	Transcriptional regulator of mmpL5	Drug efflux	[21]
	Cycloserine Terizidone	Ald	Rv2780	L-alanine dehydrogenase	Substrate shunting	[25]
		alr	Rv3423c	Alanine racemase	Target modification	[26, 27]
		ddl	Rv2981c	D-alanine-D-alanine ligase	Target modification	[27]
		cycA	Rv1704c	Bacterial D-serine/L-and D-alanine/glycine/D-cycloserine proton symporter	Mechanism not confirmed	[28]
Group C	Delamanid Pretomanid	ddn	Rv3547	Oxidative stress	Decreased drug activation	[29]
	Delamanid Pretomanid	fgd1	Rv0407	Glucose-6-phosphate oxidation	Decreased drug activation	[29]
	Imipenem/cilastatin	crfA	Rv2421c-Rv2422 intergenic	Unknown	Drug inactivation	[30]
	Amikacin, Capreomycin, Kanamycin^c	Rrs	NA	16S rRNA	Target modification	[31]
	Streptomycin	rpsL	Rv0682	12S ribosomal protein	Target modification	[32,33,34,35]
		rrs	NA	16S rRNA	Target modification	[36]
		gidB	Rv3919c	7-Methylguanosine methyltransferase	Target modification	[37]
	Ethionamide Prothionamide	ethA	Rv3854c	Mono-oxygenase	Decreased drug activation	[38, 39]
		ethR	Rv3855	Transcriptional regulatory repressor protein (TetR)	Decreased drug activation	[39]
		inhA	Rv1484	NADH-dependent enoyl-acyl carrier protein	Target amplification or modification	[10]
	Para-aminosalicylic acid (PAS)	folC	Rv2447c	Folate pathway	Decreased drug activation	[40]
		dfrA	Rv2763c	Dihydrofolate reductase	Target amplification	[40]
		thyA	Rv2764c	Thymidylate synthase	Target modification	[41, 42]
		thyX	Rv2754c	Catalyzes dTMP and tetrahydrofolate	Mitigating target inhibition	[43]
		ribD	Rv2671	Enzyme in riboflavin biosynthesis	Mitigating target inhibition	[40, 44]
Other medicines^c	Kanamycin	Eis	Rv2416c	Aminoglycoside acetyltransferase	Inactivating mutation	[45]
Other medicines^c	Capreomycin	tlyA	Rv1694	rRNA methyltransferase	Target modification	[46]

Abbreviations: MDR-TB multidrug-resistant tuberculosis, NA not applicable, RR-TB rifampicin-resistant tuberculosis, WHO World Health Organization
^aAntitubercular drugs are listed by the 2018 WHO grouping of medicines recommended for use in longer, individualized MDR-TB regimens [47]. For each drug or drug class, the specific genes in which drug-resistance mutations are commonly identified are listed with their gene name, gene number (Rv number), gene function, and the confirmed or putative mechanisms of resistance. ^bPyrazinamide and ethambutol are first-line TB drugs that also are categorized as Group C medicines for the treatment of longer MDR-TB regimens. ^cKanamycin and capreomycin are no longer recommended to be included in longer, individualized MDR/RR-TB regimens

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ISSN: 1756-994X

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