Table 1.

Drugs used for the treatment of TB as classified by the WHO [38,51,52] and Mtb genes in which resistance-conferring mutations are commonly observed

Drug	Chemical class	Mechanism of action	Mtb gene/s in which DR-conferring mutations are commonly observeda	Included in WHO-endorsed molecular diagnostics	References
First-line oral drugsb
Isoniazidc	Pyridine	Inhibition of mycolic acid synthesis	katG, inhA	Yes: MTBDRplus (V1.0 and V2.0) and Nipro NTM + MDRTB	[53, 54, 55]
Pyrazinamidec	Pyrazine	Disruption of energy homeostasis; inhibition of trans-translation and coenzyme A biosynthesis	pncA, rpsA, panD	No	[7•,53,54]
Ethambutol	Ethylenediamine	Inhibition of arabinogalactan biosynthesis	embB, ubiA	Yes: embB in MTBDRsl (V1.0 only)	[53, 54, 55]
Rifampicin	Rifamycin	Inhibition of RNA synthesis	rpoB	Yes: GeneXpert Mtb/RIF, MTBDRplus (V1.0 and V2.0) and Nipro NTM + MDRTB	[53, 54, 55]
Group A: Fluoroquinolonesd
Levofloxacin	Fluoroquinolone	Inhibition of DNA synthesis	gyrA, gyrB	Yes: gyrA MTBDRsl (V1. 0 and V2.0) gyrB in V2.0 only	[53,54,56]
Moxifloxacin	Fluoroquinolone	Inhibition of DNA synthesis	gyrA, gyrB	Yes: gyrA MTBDRsl (V1. 0 and V2.0) gyrB in V2.0 only	[53,54,56]
Gatifloxacin	Fluoroquinolone	Inhibition of DNA synthesis	gyrA, gyrB	Yes: gyrA MTBDRsl (V1. 0 and V2.0) gyrB in V2.0 only	[53,54,56]
Group B: second-line injectable drugs
Kanamycin	Aminoglycoside	Inhibition of protein synthesis	rrs, eis, whiB7	Yes: rrs in MTBDRsl (V1. 0 and V2.0) eis in V2.0 only.	[53,54,56]
Amikacin	Aminoglycoside	Inhibition of protein synthesis	rrs, eis, whiB7	Yes: rrs in MTBDRsl (V1. 0 and V2.0) eis in V2.0 only.	[53,54,56]
Capreomycin	Aminoglycoside	Inhibition of protein synthesis	rrs, tlyA	Yes: rrs MTBDRsl (V1. 0 and V2.0)	[53,54,56]
Streptomycin	Aminoglycoside	Inhibition of protein synthesis	rpsL, rrs, gidB	Yes: rrs MTBDRsl (V1. 0 and V2.0)	[53,54,56]
Group C: other core second-line agents
Clofazimine	Riminophenazine	Disruption of energy metabolism	Rv0678	No	[12•,53,54]
Linezolid	Oxazolidinone	Inhibition of protein synthesis	rrl, rplC	No	[53,54]
Cycloserine	d-Alanine analogue	Inhibition of peptidoglycan biosynthesis	alr, ddl, cycA	No	[53,54,57]
Terizidone	d-Alanine analogue	Inhibition of peptidoglycan biosynthesis	Potentially similar to cycloserine	No	[53,54]
Ethionamidec	Pyridine (thioamide)	Inhibition of mycolic acid biosynthesis	etaA/ethA, ethR, inhA	No	[53,54]
Prothionamidec	Pyridine (thioamide)	Inhibition of mycolic acid biosynthesis	Potentially similar to ethionamide	No	[53,54]
Group D: Add-on agents (do not form part of the core regimen for MDR-TB)
Pyrazinamidec	Pyrazine	Disruption of energy homeostasis; inhibition of trans-translation and coenzyme A biosynthesis	pncA, rpsA, panD	No	[7•,53,54]
Ethambutol	Ethylenediamine	Inhibition of arabinogalactan biosynthesis	embB, ubiA	Yes: embB in MTBDRsl (V1.0 only)	[53,54,55]
High-dose isoniazid	Pyridine	Inhibition of mycolic acid synthesis	katG, inhA	No	[53,54]
Bedaquiline	Diarylquinoline	Inhibition of ATP homeostasis	atpE, Rv0678	No	[12•,53,54]
Delamanidc	Nitroimidazole	Complex mechanism, including inhibition of mycolic acid biosynthesis	ddn, fdg1	No	[53,54]
Amoxicillin and clavulanate	Penicillin/β-lactam	Inhibition of cell wall biosynthesis		No	[53,54,58]
Para-aminosalicylic acidc	Salicylate	Inhibition of folic acid and thymine nucleotide metabolism	thyA, dfrA, folC, ribD	No	[53,54]
Thioacetazonec	Thiosemicarbazone	Inhibition of mycolic acid biosynthesis	Potentially ethA	No	[53,54,59,60]
Imipenem and cilastatin	Carbapenem	Inhibition of cell wall biosynthesis	Potentially Rv2421c-Rv2422	No	[53,54,61]
Meropenem and clavulanate		Inhibition of cell wall biosynthesis	Potentially Rv2421c-Rv2422	No	[53,54,61]

^aSee [26] for a list of specific mutations and associated levels of resistance.

^bRifabutin could be considered if the Mtb strain is resistant to RIF but susceptible to rifabutin [51].

^cProdrug.

^dTB antibiotic groupings as defined by the WHO policy recommendations in 2016, which focusses on treatment of DR-TB [38,51,52].