Evolution and transmission of drug-resistant tuberculosis in a Russian population

Abstract

The molecular mechanisms determining transmissibility and prevalence of drug-resistant tuberculosis in a population were investigated through whole genome sequencing of 1,000 prospectively-obtained patient isolates from Russia. Two-thirds belonged to the Beijing lineage, which was dominated by two homogeneous clades. MDR genotypes were found in 48% of isolates overall and 87% of the major clades. The most common rifampicin-resistance rpoB mutation was associated with fitness-compensatory mutations in rpoA or rpoC, and a novel intragenic compensatory substitution was identified. The proportion of MDR cases with XDR-tuberculosis was 16% overall with 65% of MDR isolates harboring eis mutations, selected by kanamycin therapy, which may drive the expansion of strains with enhanced virulence. The combination of drug resistance and compensatory mutations displayed by the major clades confer clinical resistance without compromising fitness and transmissibility, revealing a biological contribution to the tuberculosis program weaknesses driving the persistence and spread of M/XDR-tuberculosis in Russia and beyond.

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

“…In addition, the authors also demonstrated that the risk of de novo MDR acquisition before treatment is higher (approximately 22‐fold) in macaques infected with M. tuberculosis strains of lineage 2 than in animals infected with lineage 4 strains. These data are consistent with the high drug resistance potential of lineage 2 observed in many epidemiological studies (Casali et al., 2014; Merker et al., 2015). Besides the effect of genetic background, Ford et al.…”

“…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).…”

“…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). In particular, the prevalence of specific drug resistance‐associated mutations also varies within the lineage, such as the frequencies of the rpo B S531L and kat G S315T mutations are greater in the modern (typical) Beijing strains than in ancient (atypical) ones (Hillemann et al., 2005; Lipin et al., 2007; Qian et al., 2002).…”

“…Furthermore, in the absence of genetic drift (Box 1), drug‐resistant mutations with low or no biological cost are more likely to be selected and maintained in the populations (Farhat et al., 2013; Osorio et al., 2013). For instance, the predominant mutations associated with high level of drug resistance and a low or no biological cost, such as kat G S315T, rpo B S531L, rps L K43R and gyr A 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). Indeed, some of these resistance mutations do not reduce bacterial fitness in the absence of treatment (Bergval, Schuitema, Klatser, & Anthony, 2009; Huitric et al., 2006; Mariam et al., 2004).…”

“…Indeed, some of these resistance mutations do not reduce bacterial fitness in the absence of treatment (Bergval, Schuitema, Klatser, & Anthony, 2009; Huitric et al., 2006; Mariam et al., 2004). It is worth noting that MDR and XDR strains associated with outbreaks often carried these mutations explaining the successful spread of these highly drug‐resistant strains in the community (Casali et al., 2014; Cohen et al., 2015; Niehaus, Mlisana, Gandhi, Mathema, & Brust, 2015; de Vos et al., 2013). All these observations suggest that the prevalent mutations in clinical isolates have been positively selected because of their low biological cost (Figure 1a) (Farhat et al., 2013; Osorio et al., 2013).…”