Targeting hydrogen sulfide production in bacteria enhances the deadly effects of antimicrobials on drug-resistant pathogens, researchers report. The findings offer a promising strategy for developing highly effective antibiotics that also mitigate the development of antimicrobial resistance. The rise of antimicrobial resistance (AMR) to widely used clinical antibiotics is one of the most pressing threats to global public health, and by 2050, it's estimated that the annual number of worldwide deaths due to antibiotic-resistant bacteria will be nearly 10 million. However, while the prevalence of AMR has steadily grown, the number of traditional antimicrobial compounds effective for clinical use has declined, illustrating the need to identify new strategies to combat antibiotic-resistant bacterial infections. One compelling yet sparsely researched approach involves disrupting the general defense systems that protect pathogens from antibiotics. Here, Konstantin Shatalin and colleagues demonstrate one such method, targeting the hydrogen sulfide (H2S)-mediated defense system, which is present in virtually all bacteria and protects them against the toxic effects of oxidative stress. Shatalin et al. identified cystathionine γ-lyase (CSE) as the primary enzyme involved in the production of H2S in two major human pathogens - Staphylococcus aureus and Pseudomonas aeruginosa. Then, using a structure-based virtual screening approach, the authors evaluated nearly 3.2 million commercially available small molecules and identified three compounds with a marked inhibitory effect on H2S production. These inhibitors enhanced bactericidal antibiotics in vitro and in mouse models of infection. What's more, the authors found that they also suppress bacterial tolerance, disrupting biofilm formation and substantially reducing the number of persister bacteria that survive antibiotic treatment. The findings of Shatalin et al. "bring us one step closer to therapeutically targeting H2S production to bolster antibiotic activity," writes Thien-Fah Mah in a related Perspective. "Given that H2S-producing enzymes are present in most bacteria, inhibition of bacterial H2S production may be a true game-changer."