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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 ....

City Of , United Kingdom , Beckman Coulter , Roche Lightcycler , Dnase Ambion , Fortune Lab , Institutionald Program , Broad Institute , Us Department Of Defense , National Institute Of Allergy , Sciences Of The National Institutes Health , National Defense Science , L Botella Francis Crick Institute , Scientist Training Program , Imperial College London , Potts Memorial Foundation , Rockefeller University , Pfizer External Sciences , European Commission Marie Sk , Centre For Molecular Bacteriology , National Institute , Tres Cantos Open Lab Foundation , National Center , Howard Milstein Program In Chemical Biology , National Institutes Of Health , World Health Organization ,