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

Abstract

Drug-resistant tuberculosis is a threat to the control of tuberculosis globally, it develops mainly due to mutations in target genes of (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 and its promoter. Most frequent mutation in is Ser315Thr 1, while in inhA include; Thr8Cys, Ala16Gly, and Cys15Thr. Mutations in , and genes confer resistance to ethambutol. 70% of mutations in the gene occur in codon 306, 406, or 497 and include; Met306Leu, Gly43Cys, and Ser412Pro. Mutations in the , and genes mediate resistance to pyrazinamide. Frequent mutations in A include; Tyr64Ser, Phe94Ala, and Trp68Gly. MTB resistance to streptomycin (STR) occur due to mutations in the , B, and L genes. Mutations (Ala80Pro), and L (Lys43Arg) confer resistance to STR. Fluoroquinolone resistance is mediated via mutations in the A and B genes. The most common mutations in the A gene include; Gly88Cys, Ala90Val, and Ser91Pro. While those in the gyrB gene include; Glu540Val, and Asn538Asp. Mutations in the rrs and promoter region cause resistance to the kanamycin and amikacin. While mutations in the and A cause resistance to capreomycin and viomycin. Common mutations in include; Cys1402Thr, Ala1401Gly, and Gly1484Thr. While mutations in the include; Cys12Thr, Gly10Ala, and Gly37Thr.Detection of drug-target genes and their mutations has therapeutic and diagnostic value.