Drug-target genes and their spontaneous mutations associated with resistance to first-line, second-line, third-line, novel and repurposed anti-tuberculosis drugs in Mycobacterium tuberculosis resistant strains

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Review Article

Author Details : David Kajoba Mumena*, Geoffrey Kwenda, Caroline Wangari Ngugi, Andrew Kimang’a Nyerere

Volume : 8, Issue : 3, Year : 2022

Article Page : 196-204

https://doi.org/10.18231/j.ijmmtd.2022.040

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Abstract

Drug-resistant tuberculosis is a threat to the control of tuberculosis globally, it develops mainly due to mutations in target genes of Mycobacterium tuberculosis (MTB). Mutations in the rpoB gene confer resistance to rifampicin (RIF). The most frequent mutations conferring resistance to RIF include; Ser531Leu, Asp516Val, and His526Asp. Isoniazid resistance (INHr) occur most frequently due to mutations in the katG, inhA and its promoter. Most frequent mutation in katG is Ser315Thr 1, while in inhA include; Thr8Cys, Ala16Gly, and Cys15Thr. Mutations in embA, embB, embC, embR, ubiA, aftA, and iniA genes confer resistance to ethambutol. 70% of mutations in the embB gene occur in codon 306, 406, or 497 and include; Met306Leu, Gly43Cys, and Ser412Pro. Mutations in the pncA, panD, clpC1, and Rv2783c genes mediate resistance to pyrazinamide. Frequent mutations in pncA include; Tyr64Ser, Phe94Ala, and Trp68Gly. MTB resistance to streptomycin (STR) occur due to mutations in the rrs, gidB,
and rpsL genes. Mutations rrs (Ala80Pro), and rpsL (Lys43Arg) confer resistance to STR. Fluoroquinolone resistance is mediated via mutations in the gyrA and gyrB genes. The most common mutations in the gyrA gene include; Gly88Cys, Ala90Val, and Ser91Pro. While those in the gyrB gene include; Glu540Val, and Asn538Asp. Mutations in the rrs and eis promoter region cause resistance to the kanamycin and amikacin. While mutations in the rrs and tlyA cause resistance to capreomycin and viomycin. Common mutations in rrs include; Cys1402Thr, Ala1401Gly, and Gly1484Thr. While mutations in the eis include; Cys12Thr,
Gly10Ala, and Gly37Thr. Detection of drug-target genes and their mutations has therapeutic and diagnostic value.
 

Keywords: Drug-target genes, Drug-resistant tuberculosis, First-line anti-TB drugs, Fluoroquinolones, Mutations, Mycobacterium tuberculosis, Novel anti-TB drugs, Repurposed anti-TB drugs, Second-line injectable drugs

How to cite : Mumena D K, Kwenda G, Ngugi C W, Nyerere A K, Drug-target genes and their spontaneous mutations associated with resistance to first-line, second-line, third-line, novel and repurposed anti-tuberculosis drugs in Mycobacterium tuberculosis resistant strains. IP Int J Med Microbiol Trop Dis 2022;8(3):196-204

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