Genetic characterization of compensatory evolution in strains carrying rpoB Ser531Leu, the rifampicin resistance mutation most frequently found in clinical isolates

Abstract

The compensatory mutations identified in Salmonella cluster in similar locations to the additional mutations found in M. tuberculosis isolates. These new data strongly support the idea that many of the previously identified rpoA, rpoB and rpoC mutations in rifampicin-resistant M. tuberculosis (rpoB S531L) are indeed fitness-compensatory mutations.

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

“…Indeed, it was reported that part of rifampicin‐resistant isolates with a rpo B mutation also carry a nonsynonymous mutation in the rpo A or rpo C gene in South Africa (27.1%, 89/329), China (27.8%, 89/320) and Korea (39.4%, 67/170) (Comas et al., 2012; Li et al., 2016; Song et al., 2014). In addition, clinical isolates that carry mutations in the RRDR of rpo B and also in rpo A/ rpo C display higher competitive fitness in vitro and in vivo compared with laboratory‐generated rifampicin‐resistant mutants that carry only the same rpo B RRDR mutation and that belong to the same phylogenetic lineage (Brandis & Hughes, 2013; Comas et al., 2012; Song et al., 2014). These data suggest that mutations in the rpo A/ rpo C genes are fitness‐compensatory mutations that alleviate the costs of rpo B mutations.…”

“…These data suggest that mutations in the rpo A/ rpo C genes are fitness‐compensatory mutations that alleviate the costs of rpo B mutations. 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).…”

“…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). It is worth noting that compensatory mutations are more commonly identified in the dominant MDR, pre‐XDR and XDR clones in high MDR TB burden countries, suggesting that high drug‐resistant mutants harbouring these mutations can be successfully transmitted in human populations (Casali et al., 2014; Cohen et al., 2015; Comas et al., 2012; Klopper et al., 2013; Li et al., 2016; de Vos et al., 2013).…”

“…These authors also found some double mutants bearing higher biological cost, which can be a sign of negative epistasis. Furthermore, the acquisition of a secondary mutation (linked or not linked to drug resistance) in the same gene, for example rpo B, was associated with a reduction of biological cost (Brandis & Hughes, 2013; Song et al., 2014). …”

A Microbiological Revolution Meets an Ancient Disease: Improving the Management of Tuberculosis with Genomics

“…In contrast, another study reported that phenotypic testing indicated isoniazid resistance, but WGS failed to identify the mutation responsible (45). Mutations conferring drug resistance are known to come at the cost of a loss in an organism's fitness; however, recent genomic studies revealed that compensatory mutations can occur which overcome the loss of fitness and create a "perfect storm" of resistant isolates without reduced fitness (42,(46)(47)(48). Furthermore, it has been shown that M. tuberculosis strains of different lineages can differ in their virulence, acquiring mutations conferring antibiotic resistance, a delayed host immune response, enhanced transmissibility, and more severe disease at different rates (49)(50)(51).…”