Multiform antimicrobial resistance from a metabolic mutation.
| Publication Type | Academic Article |
| Authors | Schrader S, Botella H, Jansen R, Ehrt S, Rhee K, Nathan C, Vaubourgeix J |
| Journal | Sci Adv |
| Volume | 7 |
| Issue | 35 |
| Date Published | 08/27/2021 |
| ISSN | 2375-2548 |
| Keywords | Anti-Bacterial Agents, Drug Resistance, Bacterial |
| Abstract | A critical challenge for microbiology and medicine is how to cure infections by bacteria that survive antibiotic treatment by persistence or tolerance. Seeking mechanisms behind such high survival, we developed a forward-genetic method for efficient isolation of high-survival mutants in any culturable bacterial species. We found that perturbation of an essential biosynthetic pathway (arginine biosynthesis) in a mycobacterium generated three distinct forms of resistance to diverse antibiotics, each mediated by induction of WhiB7: high persistence and tolerance to kanamycin, high survival upon exposure to rifampicin, and minimum inhibitory concentration-shifted resistance to clarithromycin. As little as one base change in a gene that encodes, a metabolic pathway component conferred multiple forms of resistance to multiple antibiotics with different targets. This extraordinary resilience may help explain how substerilizing exposure to one antibiotic in a regimen can induce resistance to others and invites development of drugs targeting the mediator of multiform resistance, WhiB7. |
| DOI | 10.1126/sciadv.abh2037 |
| PubMed ID | 34452915 |
| PubMed Central ID | PMC8397267 |