Effect of Mutation and Genetic Background on Drug Resistance in Mycobacterium tuberculosis

Abstract

Bacterial factors may contribute to the global emergence and spread of drug-resistant tuberculosis (TB). Only a few studies have reported on the interactions between different bacterial factors. We studied drug-resistant Mycobacterium tuberculosis isolates from a nationwide study conducted from 2000 to 2008 in Switzerland. We determined quantitative drug resistance levels of firstline drugs by using Bactec MGIT-960 and drug resistance genotypes by sequencing the hot-spot regions of the relevant genes. We determined recent transmission by molecular methods and collected clinical data. Overall, we analyzed 158 isolates that were resistant to isoniazid, rifampin, or ethambutol, 48 (30.4%) of which were multidrug resistant. Among 154 isoniazid-resistant strains, katG mutations were associated with high-level and inhA promoter mutations with low-level drug resistance. Only katG(S315T) (65.6% of all isoniazid-resistant strains) and inhA promoter ؊15C/T (22.7%) were found in molecular clusters. M. tuberculosis lineage 2 (includes Beijing genotype) was associated with any drug resistance (adjusted odds ratio [OR], 3.0; 95% confidence interval [CI], 1.7 to 5.6; P < 0.0001). Lineage 1 was associated with inhA promoter ؊15C/T mutations (OR, 6.4; 95% CI, 2.0 to 20.7; P ‫؍‬ 0.002). We found that the genetic strain background influences the level of isoniazid resistance conveyed by particular mutations (interaction tests of drug resistance mutations across all lineages; P < 0.0001). In conclusion, M. tuberculosis drug resistance mutations were associated with various levels of drug resistance and transmission, and M. tuberculosis lineages were associated with particular drug resistance-conferring mutations and phenotypic drug resistance. Our study also supports a role for epistatic interactions between different drug resistance mutations and strain genetic backgrounds in M. tuberculosis drug resistance.

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

“…The mutation frequency and type vary in function of different parameters, such as the geographic region, the drug resistance pattern and genetic background (Fenner et al., 2012; Hillemann, Kubica, Rusch‐Gerdes, & Niemann, 2005; Lipin, Stepanshina, Shemyakin, & Shinnick, 2007; Qian et al., 2002). Despite the large diversity of mutation patterns globally, only few specific mutations are predominant (Table 2) (Sandgren et al., 2009; Zhang & Yew, 2015).…”

“…In addition, different mutations in the same gene or in different genes can produce similar drug resistance phenotypes (Sandgren et al., 2009; Zhang & Yew, 2015), but can be associated with similar or different drug resistance levels (Fenner et al., 2012; Gagneux, Long, et al., 2006; Huitric, Werngren, Jureen, & Hoffner, 2006). For instance, some mutations in rpo B gene, such as rpo B S531L, H526Y, H526D and H526R, are often associated with high levels of rifampicin resistance, while mutations including rpo B L511P, H526L, H526N, L533P and I572F are generally linked to low levels of rifampicin resistance (Huitric et al., 2006; Van Deun et al., 2009).…”

“…For instance, some mutations in rpo B gene, such as rpo B S531L, H526Y, H526D and H526R, are often associated with high levels of rifampicin resistance, while mutations including rpo B L511P, H526L, H526N, L533P and I572F are generally linked to low levels of rifampicin resistance (Huitric et al., 2006; Van Deun et al., 2009). Similar to that, kat G mutations are often associated with high levels of isoniazid resistance, whereas inh A mutations with low levels (Fenner et al., 2012; van Soolingen et al., 2000; Vilcheze & Jacobs, 2014). …”

“…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).…”

“…Thus, lineage 2 could be better adapted to compensate for the loss or reduced activity of this catalase‐peroxidase enzyme in the context of isoniazid resistance. This hypothesis could also explain why the Beijing strains are generally strongly associated with resistance to isoniazid, regardless of the type of kat G resistant‐associated mutations and country (Fenner et al., 2012; Gagneux, Burgos, et al., 2006; Mokrousov et al., 2002; Ribeiro et al., 2014; van Soolingen et al., 2000). …”