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.

Frequency of rpoB, katG, and inhA Gene Polymorphisms Associated with Multidrug-Resistant Mycobacterium tuberculosis Complex Isolates among Ethiopian TB Patients: A Systematic Review

“…The increased proportion of resistance to RIF, INH, and MDR-TB in patients among new and previously treated cases indicates a need for better patient management to help prevent the evolution of drug-resistance TB [ 22 , 23 , 26 ]. However, the increasing frequencies of rpoB, katG, and inhA gene mutations in MDR-TB appear to vary by geographical locations and tie of sample collection [ 7 ]. This would permit modifying molecular tests to specific geographical regions and better multidrug combinatory therapy recommendations.…”

“…However, to date, the challenging condition for the global prevention and control program of TB and the major factors fueling the TB epidemic is the emergence and spread of multidrug- and extensively drug-resistance tuberculosis (MDR/XDR-TB) strains of MTBC on new and previously treated cases [ 5 ]. Early case detection and treatment of MDR/XDR-TB cases is essential to prevent and control the transmission of TB [ 6 ], and has become an urgent public health problem in developing countries including Ethiopia, due to their complex diagnostic and treatment obstacles [ 7 ]. Some of the significant factors associated with increasing the development of drug-resistant tuberculosis (DR-TB) and the risk of direct transmission of DR-TB are an increase of TB with HIV-1 co-infection, overcrowded living conditions, lack of or poor access to healthcare such as lack of DR-TB diagnostic tools and delaying drug susceptibility testing (DST) practices, inadequate administration of anti-TB therapy regimens with inappropriate prescription of anti-TB drugs and patient compliance [ 8 ], weak TB prevention and control program, and high prevalence of diabetes mellitus, alcoholism, and smoking [ 9 , 10 ].…”

Insights into the in-vitro Susceptibility and Drug–Drug Interaction Profiles Against Drug-Resistant and Susceptible Mycobacterium tuberculosis Clinical Isolates in Amhara, Ethiopia

“…However, the level of drug resistance can impact treatment choices and outcomes. The treatment of DR-TB patients requires an individualized regimen that depends on the level of inhibitory for drug resistance, TB/HIV co-infection status, drug–drug interactions, 10 and the drug’s toxicity to the patient that may lead to treatment interruptions and influence the treatment success. 11 , 12 This in turn could promote the development of drug resistance.…”

Application of Next Generation Sequencing for Diagnosis and Clinical Management of Drug-Resistant Tuberculosis: Updates on Recent Developments in the Field

“…Other mechanisms of drug resistance include efflux mediated resistance, deficient DNA repair systems and other compensatory mechanisms ( Dookie et al, 2018 ; Ghajavand et al, 2019b ). Epistasis and intrinsic cell wall impermeability further contributes to drug resistance ( Al-Saeedi and Al-Hajoj, 2017 ; Seid and Berhane, 2021 ). These may be a consequence of sub-optimal concentrations of anti-TB drugs from altered host pharmacokinetics (PK) ( Liu et al, 2006 ; Trauner et al, 2017 ).…”