Abstract
AbstractDrug resistant infections represent one of the most challenging medical problems of our time. D-cycloserine is an antibiotic used for decades without appearance and dissemination of antibiotic resistant strains, making it an ideal model compound to understand what drives resistance evasion. We investigated whyMycobacterium tuberculosisfails to become resistant to D-cycloserine. To address this question we employed a combination of bacterial genetics, genomics, biochemistry and fitness analysisin vitro, in macrophages and in mice. Altogether, our results suggest that the ultra-low mutation frequency associated with D-cycloserine resistance is the dominant factor delaying the appearance of clinical resistance to this antibiotic in bacteria infecting humans, and not lack of potential compensatory mechanisms.One Sentence SummaryWe show that the lack of D-cycloserine resistance inMycobacterium tuberculosisis due its ultra-low mutation frequency rather than lack of compensatory mechanisms.
Publisher
Cold Spring Harbor Laboratory