Abstract
At present, the successful transmission of drug‐resistant Mycobacterium tuberculosis, including multidrug‐resistant (MDR) and extensively drug‐resistant (XDR) strains, in human populations, threatens tuberculosis control worldwide. Differently from many other bacteria, M. tuberculosis drug resistance is acquired mainly through mutations in specific drug resistance‐associated genes. The panel of mutations is highly diverse, but depends on the affected gene and M. tuberculosis genetic background. The variety of genetic profiles observed in drug‐resistant clinical isolates underlines different evolutionary trajectories towards multiple drug resistance, although some mutation patterns are prominent. This review discusses the intrinsic processes that may influence drug resistance evolution in M. tuberculosis, such as mutation rate, drug resistance‐associated mutations, fitness cost, compensatory mutations and epistasis. This knowledge should help to better predict the risk of emergence of highly resistant M. tuberculosis strains and to develop new tools and strategies to limit the development and spread of MDR and XDR strains.
Highlights
Tuberculosis (TB), an infectious airborne disease mainly caused by Mycobacterium tuberculosis, is one of the world’s deadliest infectious diseases
We focus on the intrinsic factors influencing the drug resistance evolution in M. tuberculosis, the mutation rate, drug resistance-associated mutations, fitness cost of resistance mutations, compensatory mutations and epistasis (Box 1)
In M. tuberculosis, epidemiological and molecular data have shown the emergence and the successful spread of MDR/ XDR clones belonging to Beijing or LAM families carrying specific mutations associated with high level of drug resistance and compensatory mutations (Casali et al, 2014; Cohen et al, 2015; Eldholm et al, 2015)
Summary
Tuberculosis (TB), an infectious airborne disease mainly caused by Mycobacterium tuberculosis, is one of the world’s deadliest infectious diseases. The predominant mutations associated with high level of drug resistance and a low or no biological cost, such as katG S315T, rpoB S531L, rpsL K43R and gyrA D94G (conferring resistance to isoniazid, rifampicin, streptomycin and fluoroquinolones respectively), are more frequently found in clinical drug-resistant isolates (Billington et al, 1999; Bottger et al, 1998; Campbell et al, 2011; Casali et al, 2014; Gagneux, Burgos, et al, 2006; Gagneux, Long, et al, 2006; Mariam et al, 2004; Pym et al, 2002).
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