Quadruple-first line drug resistance in Mycobacterium tuberculosis in Vietnam: What can we learn from genes?

Insights into the processes that drive the evolution of drug resistance in Mycobacterium tuberculosis

“…(b) Under drug pressure, positive epistasis may favour the acquisition of compensatory mutations to alleviate the fitness cost exerted by certain drug resistance‐associated mutations. (c) Driven by positive epistasis, drug‐resistant mutants are likely to be more prone to accumulate drug resistance‐associated mutations at higher frequencies (Nguyen, Nguyen, et al., 2017; Trindade et al., 2009)…”

“…For instance, the kat G S315T is prevalent in lineage 2, conversely the inh A‐15 mutation is associated mostly with lineage 1 (Casali et al., 2014; Fenner et al., 2012; Gagneux, Burgos, et al., 2006; Mokrousov et al., 2002; Nguyen, Nguyen, et al., 2017). Similar to that, the rpo B S531L mutation is observed mainly in lineage 2 compared with other lineages, while the rpo B D516V mutation is more frequent in lineage 4 (LAM family) (Casali et al., 2014; Hillemann et al., 2005; Lipin et al., 2007).…”

“…Furthermore, genetic reconstructions in a Salmonella model demonstrated that mutations not only in rpo A and rpo C, but also in rpo B are associated with higher growth rate (Brandis & Hughes, 2013; Brandis et al., 2012). In fact, many previous studies showed that rifampicin‐resistant M. tuberculosis clinical isolates carry multiple (double, triple and quadruple) mutations in the rpo B gene (Bahrmand, Titov, Tasbiti, Yari, & Graviss, 2009; Casali et al., 2014; Nguyen, Nguyen, et al., 2017; Song et al., 2014). This could be the result of compensatory mechanisms to alleviate the fitness cost exerted by specific mutations (Brandis & Hughes, 2013; Brandis et al., 2012).…”

“…Nevertheless, for almost all drug resistance‐associated genes, the predominance of some specific mutations, generally known to be associated with high level of resistance and low biological cost, has been described (see Table 2). As a result, combinations of at least two specific mutations, such as rpo B531, kat G315, rps L43, emb B306 and gyr A94, are favoured (Casali et al., 2014; Cohen et al., 2015; Nguyen, Nguyen, et al., 2017). Although the quality of the treatment undoubtedly plays a role in the emergence of particular drug resistance mutations, the strains with drug resistance‐associated mutations seem to have higher propensity to accumulate other drug resistance mutations in the same gene or in different genes (Bahrmand et al., 2009; Jagielski et al., 2014; Nguyen, Nguyen, et al., 2017; Shen et al., 2007).…”

“…As a result, combinations of at least two specific mutations, such as rpo B531, kat G315, rps L43, emb B306 and gyr A94, are favoured (Casali et al., 2014; Cohen et al., 2015; Nguyen, Nguyen, et al., 2017). Although the quality of the treatment undoubtedly plays a role in the emergence of particular drug resistance mutations, the strains with drug resistance‐associated mutations seem to have higher propensity to accumulate other drug resistance mutations in the same gene or in different genes (Bahrmand et al., 2009; Jagielski et al., 2014; Nguyen, Nguyen, et al., 2017; Shen et al., 2007). For instance, the kat G315, emb B306 or pnc A mutations are more frequently observed in MDR than in non‐MDR isolates (Hazbon et al., 2006; Nguyen, Contamin, et al., 2017; Salvatore et al., 2016; Shen et al., 2007).…”