“On demand” redox buffering by H₂S contributes to antibiotic resistance revealed by a bacteria-specific H₂S donor

Understanding the mechanisms of antimicrobial resistance (AMR) will help launch a counter-offensive against human pathogens that threaten our ability to effectively treat common infections. Herein, we report bis(4-nitrobenzyl)sulfanes, which are activated by a bacterial enzyme to produce hydrogen sulfide (H₂S) gas. We found that H₂S helps maintain redox homeostasis and protects bacteria against antibiotic-triggered oxidative stress "on demand", through activation of alternate respiratory oxidases and cellular antioxidants. We discovered, a hitherto unknown role for this gas, that chemical inhibition of H₂S biosynthesis reversed antibiotic resistance in multidrug-resistant (MDR) uropathogenic <i>Escherichia coli</i> strains of clinical origin, whereas exposure to the H₂S donor restored drug tolerance. Together, our study provides a greater insight into the dynamic defence mechanisms of this gas, modes of antibiotic action as well as resistance while progressing towards new pharmacological targets to address AMR.