The treatment of bacterial infections can be impeded by the presence of persister cells, which have slowed their metabolism in response to stress and can survive antibiotic exposure even without being resistant. To make persisters more susceptible to antibiotics, Shatalin and Nuthanakanti et al. sought to inhibit the production of hydrogen sulfide (H2S), which bacteria use to protect against oxidative stress. Inactivation of bacterial cystathionine γ-lyase (bCSE), the major producer of H2S in the pathogens Staphylococcus aureus and Pseudomonas aeruginosa, sensitized these bacteria to low doses of common bactericidal antibiotics. Three validated leads originating from an in silico compound screen, each with an indole moiety, potently inhibited bCSE via an allosteric mechanism in which the compounds prevent a catalytically necessary rearrangement in the active site. Furthermore, these compounds inhibited H2S production in S. aureus and P. aeruginosa, disrupted biofilm formation, and potentiated the activity of various antibiotics both in cell culture and in mouse models of infection. The identification of inhibitors that target persisters holds promise for the development of new drugs to treat challenging bacterial infections.