Tuberculosis treatment failure associated with evolution of antibiotic resilience.

Abstract

The widespread use of antibiotics has placed bacterial pathogens under intense pressure to evolve new survival mechanisms. Genomic analysis of 51,229 <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>)clinical isolates has identified an essential transcriptional regulator, <i>Rv1830</i>, herein called <i>resR</i> for resilience regulator, as a frequent target of positive (adaptive) selection. <i>resR</i> mutants do not show canonical drug resistance or drug tolerance but instead shorten the post-antibiotic effect, meaning that they enable <i>Mtb</i> to resume growth after drug exposure substantially faster than wild-type strains. We refer to this phenotype as antibiotic resilience. ResR acts in a regulatory cascade with other transcription factors controlling cell growth and division, which are also under positive selection in clinical isolates of <i>Mtb</i>. Mutations of these genes are associated with treatment failure and the acquisition of canonical drug resistance.