Role of hydrogen sulfide in bacterial antibiotic tolerance: from mechanisms to therapeutic targeting.

Fengshan Li, Jiawen Shen, Huiru Cao, Xiaoqing Wang, Yulu Du, Yalong Liu, Tianyu Dong, Hua Tian, Salwa E Gomaa, Xianghui Li, Guanbin Qi, Chaonan Ma

Journal: Frontiers in cellular and infection microbiology 2026;16():1875957

PMID: 42597558

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Abstract

Hydrogen sulfide (H₂S) is fundamentally a gaseous signaling molecule in bacteria. Recent studies have reported that H₂S is a key mediator of bacterial antibiotic tolerance, making it a promising strategic target for overcoming tolerance, eliminating persisters, and restoring antibiotic efficacy. We systematically review recent advances in H₂S-mediated multidrug tolerance mechanisms, highlighting three core pathways: iron chelation for antioxidant defense, reactive sulfur species-mediated antibiotic inactivation and efflux pump activation, and metabolic dormancy induced by respiratory inhibition, and note that recent advances in H₂S fluorescent probes have provided important tools for monitoring intracellular H₂S changes in bacteria under antibiotic stress. Furthermore, this review systematically summarizes recent advances in the development of novel inhibitors targeting intracellular H₂S biosynthesis in bacteria.

Address: Department of Pulmonary and Critical Care Medicine, Huaihe Hospital of Henan University, Henan University, Kaifeng, China.; Henan International Joint Laboratory for Nuclear Protein Regulation, School of Basic Medical Sciences, Henan University, Kaifeng, Henan, China.; Department of Pulmonary and Critical Care Medicine, the First Affiliated Hospital of Henan University, Kaifeng, China.; Department of Pulmonary and Critical Care Medicine, Huaihe Hospital of Henan University, Henan University, Kaifeng, China.; Department of Microbiology and Immunology, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt.; Department of Pulmonary and Critical Care Medicine, Huaihe Hospital of Henan University, Henan University, Kaifeng, China.; Oncology Department, Kaifeng Central Hospital, Kaifeng, China.

DOI: 10.3389/fcimb.2026.1875957

MeSH Terms: Hydrogen Sulfide, Anti-Bacterial Agents, Bacteria, Drug Resistance, Bacterial, Drug Resistance, Multiple, Bacterial, Humans