Molecular Targets Related Drug Resistance Mechanisms in MDR-, XDR-, and TDR-Mycobacterium tuberculosis Strains

Abstract

Tuberculosis (TB) is a formidable infectious disease that remains a major cause of death worldwide today. Escalating application of genomic techniques has expedited the identification of increasing number of mutations associated with drug resistance in Mycobacterium tuberculosis. Unfortunately the prevalence of bacillary resistance becomes alarming in many parts of the world, with the daunting scenarios of multidrug-resistant tuberculosis (MDR-TB), extensively drug-resistant tuberculosis (XDR-TB) and total drug-resistant tuberculosis (TDR-TB), due to number of resistance pathways, alongside some apparently obscure ones. Recent advances in the understanding of the molecular/ genetic basis of drug targets and drug resistance mechanisms have been steadily made. Intriguing findings through whole genome sequencing and other molecular approaches facilitate the further understanding of biology and pathology of M. tuberculosis for the development of new therapeutics to meet the immense challenge of global health.

An overview of new antitubercular drugs, drug candidates, and their targets

“…Clofazimine also shows cross‐resistance with bedaquiline because of overexpression of the MmpL5 efflux pump. Recently mutations in pepQ gene were also proposed to be responsible for cross‐resistance between bedaquiline and clofazimine …”

“…The isopropylimino group at C‐3 position is responsible for the cationic amphiphilic character of the molecule. Cationic amphiphilic drugs are characterized by a hydrophobic aromatic ring and a hydrophilic side chain carrying an ionizable amine group …”

“…Recently mutations in pepQ gene were also proposed to be responsible for cross-resistance between bedaquiline and clofazimine. 170,171…”

“…Cationic amphiphilic drugs are characterized by a hydrophobic aromatic ring and a hydrophilic side chain carrying an ionizable amine group. 170,178…”

Deletion of RsmE 16S rRNA methyltransferase leads to low level increase in aminoglycoside resistance inMycobacterium smegmatis

“…Any resistance towards the second line of drugs compounds the problem towards extensively drug resistant disease (XDR-TB). Resistance to fluoroquinolones may occur due to mutations in gyrases (Nosova et al, 2013;Zhang and Yew 2015), to kanamycin by overexpression of eis drug-modifying enzyme (Sowajassatakul et al, 2014;Kambli et al, 2016) or of efflux pumps (Louw et al, 2009;Reeves et al, 2013), and to other aminoglycosides by modification of target binding site through mutations in rrs (Gygli et al, 2017;Hameed et al, 2018), ribosomal protein genes (Finken et al, 1993) or changes in rRNA methylation pattern (Buriánková et al, 2004;Maus et al, 2005;Okamoto et al, 2007).…”