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.

Keywords: Mycobacterium tuberculosis; comorbidities; drug resistance; drug targets; molecular; therapeutic.

Figure 1

Proteins/RNAs/genes related to anti-TB drugs. 2'-O-methyltransferase TlyA (tlyA), Ribosomal RNA 16S (rrs), 30S ribosomal protein S12 RpsL (rpsL), 50S ribosomal protein L3 RplC (rplC), arabinosyltransferases EmbABC (embABC), DNA topoisomerase II /DNA gyrases GyrA, GyrB (gyrA, gyrB), RNA polymerase β-subunit RpoB (rpoB), catalase-peroxidase KatG (katG), alkyl hydroperoxidase C AhpC (ahpC), NADH dehydrogenase Ndh (ndh), enoyl-acyl-carrier protein-reductase InhA (inhA), β-ketoacyl ACP synthase KasA (kasA), Monooxygenase EthA (ethA), Transcriptional regulatory repressor protein EthR (ethR), Pyrazinamidase/nicotinamidase PZase PncA (pncA), 30S ribosomal protein S1 RpsA (rpsA), GpsI (polynucleotide phosphorylase, gpsI) and Pnpase (Rv2783c), ClpC1 (ATP-dependent protease ATP-binding subunit, clpC1), Conserved protein (Rv0678, Rv0678), folate synthase FolC (folC), nonclassical transpeptidase (LdtMt2), D-alanyl-D-alanine ligase DdlA (ddlA), transmembrane transport protein MmpL3 (mmpL3), Cell division protein FtsZ (ftsZ), dTDP-4-dehydrorhamnose 3,5-epimerase RmlC (rmlC), Acetyl/propionyl-CoA carboxylase (β-subunit) AccD6 (accD6), Deazaflavin-dependent nitroreductase Ddn (ddn), Mycolic acid synthase PcaA (cyclopropane synthase) (pcaA), CTP synthetase for Pyrimidine biosynthesis PyrG (pyrG), Serine/threonine-protein kinase PknG (pknG), Two component sensor histidine kinase DevS (devS), Malate synthase GlcB (glcB), ATP synthase C chain AtpE (atpE), MEP cytidylyltransferase IspD (ispD), Polyketide synthase Pks13 (pks13), Fatty-acid-AMP ligase FadD32 (fatty-acid-AMP synthetase) (fadD32), Hypothetical protein (Rv3788), ubiquinol-cytochrome C reductase QcrB (qcrB).