Molecular Mechanisms of Genetic Interaction (Epistasis) in the Evolution and Management of Antibiotic Resistance Tuberculosis: Current Consequence and Future Perspectives

Abstract

Tuberculosis (TB) is an infectious chronic human disease caused by Mycobacterium tuberculosis (MTB) bacteria. M. tuberculosis has a great capability of resistance with plentiful natural and acquired mechanisms in their genome that contribute to the spread of highly drug resistance strains and became major public health concern. The majority of drug resistance in M. tuberculosis strains has been resulted from a numbers of chromosomal mutation events most of which are due to the mechanisms of epistasis that leads to the creation of resistance genes to anti-TB drugs. Epistasis can occur when two or more mutations interact with each other to express new phenotypic traits to modify their fitness cost. Thus, the objective of this review was to assessed the molecular mechanisms of epistasis and its consequences in the evolution and managements of antibiotic resistance-TB. The epistatic interactions within and between resistance gene mutations in M. tuberculosis could be detected by co-culture competitive fitness experimental assay under optimal growth conditions that showed either significantly negative or improving deleterious positive fitness effect. Molecular mechanisms of epistatic interaction could have important practical consequences in the trajectory of drug resistance, evolution of antimicrobial resistance and management of antibiotic resistance-TB. Understanding the evolution of M. tuberculosis under antibiotic treatments is a burning issue today. Unlike the deleterious positive epistasis, the beneficial negative epistatic interaction of resistance gene mutations under multidrug therapy method and/or collateral drug sensitivity approaches based on the knowledge of drug combinations help to mitigate the spread of drug-resistant strains, reduce treatment duration, minimize adverse drug effects on evolution of MDR/XDR-TB and improve treatment outcomes of TB patients.