Multiform antimicrobial resistance from a metabolic mutation

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.

Automated summary

A critical challenge faced by microbiology and medicine is how to cure infections caused by bacteria that survive antibiotic treatment by persistence or tolerance. Research has found that even a single base change in a gene encoding a component of a metabolic pathway can confer multiple forms of resistance to multiple antibiotics with different targets. This extraordinary resilience may help explain why substerilizing exposure to one antibiotic in a regimen can induce resistance to others, and could lead to the development of drugs targeting the mediator of multiform resistance, WhiB7.