H₂S-producing enzymes in bacteria have been shown to be closely engaged in the process of microbial survival and antibiotic resistance. However, no inhibitors have been discovered for these enzymes, e.g., 3-mercaptopyruvate sulfurtransferase (MST). In the present study, we identified several classes of inhibitors for Escherichia coli MST (eMST) through high-throughput screening of ∼26,000 compounds. The thiazolidinedione-type inhibitors were found to selectively bind to Arg178 and Ser239 residues of eMST but hardly affected human MST. Moreover, the pioglitazone of this class concentration dependently accumulates the 3-mercaptopyruvate substrate and suppresses the H₂S and reactive sulfane sulfur products in bacteria. Importantly, pioglitazone could potentiate the level of reactive oxygen species in cellulo and consequently enhance the antimicrobial effects of gentamicin and macrophages in culture. This study has identified the bioactive inhibitor of eMST, paving the way for the pharmacological targeting of eMST to synergistically control the survival of E. coli.

细菌中产生H ₂ S的酶已被证明与微生物存活和抗生素耐药性密切相关。然而，尚未发现这些酶的抑制剂，例如3-巯基丙酮酸硫转移酶（MST）。在本研究中，我们通过对约26,000种化合物进行高通量筛选，鉴定了几类大肠埃希菌MST（eMST）抑制剂。发现噻唑烷二酮型抑制剂选择性结合eMST的Arg178和Ser239残基，但几乎不影响人MST。此外，该浓度的吡格列酮依赖性地积聚3-巯基丙酮酸底物并抑制H _2。硫与反应性硫磺细菌中的产物。重要的是，吡格列酮可以增强纤维素中活性氧的含量，从而增强庆大霉素和培养物中巨噬细胞的抗菌作用。这项研究确定了eMST的生物活性抑制剂，为eMST的药理靶向协同协同控制大肠杆菌的生存铺平了道路。