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Description
Rifampicin (RIF) is a first-line drug used to treat Mycobacterium tuberculosis (Mtb). Resistance to RIF is predominantly associated with chromosomal mutations in the rpoB gene. This study sought to determine the mutations that explained RIF resistance in a set of 347 isolates (303 resistant, 44 susceptible). The promoter regions of three efflux pump genes, emrB, pstB, and drrA, were also examined for mutations that may confer RIF resistance. Eight RIF-resistant isolates lacked genetic explanation for their resistance but had good sequencing coverage, and eight RIF-susceptible isolates contained mutations reported to confer resistance to RIF. The lack of explanation for the resistance of several isolates raises the questions as to whether current diagnostic methods are reliable enough to detect low-level resistance to rifampicin, and whether there are other mechanisms of resistance that are not yet fully understood. For this reason, the DNA methylation patterns of our isolates, especially those lacking explanation, were examined for associations that would provide insight into other potential mechanisms of resistance. It was found that the unexplained RIF-R isolates had methylation patterns that were comparable to reported drug-tolerant populations, and lacked methylation of several drug effluxing pump genes, suggesting a possible combination of both drug tolerance and (over)expression of efflux pumps as a potential mechanism of resistance. The mechanisms of drug resistance in Mtb maybe more dynamic than currently presumed, and the common mechanism of genetic mutation may eventually be outcompeted by a more adaptive and virulent population of Mtb that is able to respond to a changing environment more quickly. This includes the more immediate benefits that might result from both drug effluxing and the control of gene expression via methylation (which may contribute to the potential for drug tolerance); both of these mechanisms may allow the bacteria to survive long enough to either develop more permanent solutions like genetic mutations or to persist in the presence of the drug during the treatment period. Though these conclusions are daunting, they may provide a more robust picture of the evolution and adaptation of Mtb that could help prevent the exacerbation of drug resistance in the future.
