Antibiotic resistance threatens to reverse the immense medical advances antibiotics have enabled. Resistance can manifest as an increase in the concentration of antibiotic required to stop growth of a bacterial population (MIC-shifted resistance) or a decrease in the rate of killing (high survival) for the entire population (tolerance) or a subpopulation (persistence). Mechanisms of MIC-shifted resistance are well-studied, but those behind high survival, which drives prolonged treatment times, infection recurrence, and development of mutations conferring MIC-shifted resistance, remain enigmatic. We developed a forward-genetic method for efficient isolation of high survival mutants in any culturable bacterial species. In Mycobacterium smegmatis, loss of function of nonessential genes in arginine biosynthesis elicited WhiB7-mediated tolerance and high persistence to kanamycin, high survival upon exposure to rifampicin, and MIC-shifted resistance to clarithromycin. Our results point to WhiB7 as a central mediator of multiple forms of resistance to multiple antibiotics and reveal that perturbation of one pathway can induce resistance to antibiotics targeting other pathways, raising implications for formulation of effective antibiotic combinations.