Abstract
AbstractDrug resistant infections represent one of the most challenging medical problems of our time.D-cycloserine is an antibiotic used for six decades without significant appearance and dissemination of antibiotic resistant strains, making it an ideal model compound to understand what drives resistance evasion. We therefore investigated whyMycobacterium tuberculosisfails to become resistant toD-cycloserine. To address this question, we employed a combination of bacterial genetics, genomics, biochemistry and fitness analysis in vitro, in macrophages and in mice. Altogether, our results suggest that the ultra-low rate of emergence of D-cycloserine resistance mutations is the dominant biological factor delaying the appearance of clinical resistance to this antibiotic. Furthermore, we also identified potential compensatory mechanisms able to minimize the severe fitness costs of primaryD-cycloserine resistance conferring mutations.
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry
Reference53 articles.
1. Klein, E. Y. et al. Global increase and geographic convergence in antibiotic consumption between 2000 and 2015. Proc. Natl Acad. Sci. USA 115, E3463–e3470 (2018).
2. Baker, S. Infectious disease. A return to the pre-antimicrobial era? Science 347, 1064–1066 (2015).
3. O’Neill, J., Davies, S., Rex, J., White, L.J., and Murray, R. Review on antimicrobial resistance, tackling drug-resistant infections globally: final report and recommendations. London: Wellcome Trust and UK Government. 1–84 (2016).
4. Lewis, K. Platforms for antibiotic discovery. Nat. Rev. Drug Disco. 12, 371–387 (2013).
5. Laxminarayan, R. et al. Antibiotic resistance—the need for global solutions. Lancet Infect. Dis. 13, 1057–1098 (2013).
Cited by
23 articles.
订阅此论文施引文献
订阅此论文施引文献，注册后可以免费订阅5篇论文的施引文献，订阅后可以查看论文全部施引文献