[ODP7B] b. Drug Resistance

[ODP-210] Identification of β-lactam ring opened carbothioic S-acids mediated by cysteine hydropersulfide

○Katsuhiko Ono¹, Hiroyasu Tsutsuki¹, Tianli Zhang¹, Takaaki Akaike², Tomohiro Sawa¹ (¹Dept. Microbiol., Grad. Sch. Med. Sci., Kumamoto Univ., ²Dept. Envir. Med. Mol. Toxicol., Tohoku Univ., Grad. Sch. Med.)

Antibiotic resistance is a global concern. Hydrogen sulfide (H₂S) formed during sulfur metabolisms in bacteria has been considered to implicate for the development of resistant against β-lactam antibiotics, whereas detail mechanisms remains unclear. Here we demonstrated that cysteine hydropersulfide (CysSSH) derived from reaction between cystine and H₂S efficiently reacted with penicillin G to form a novel product β-lactam ring opened penicillin G carbothioic S-acid (PG-COSH). Formation of PG-COSH is specific for CysSSH, and was not observed for reaction between penicillin G and H₂S, cysteine, or cystine. Bacterial growth assay revealed that PG-COSH showed no antibacterial activity. We developed sensitive detection method for PG-COSH by means of liquid chromatography-tandem mass spectrometry with monobromobimane derivatization. Importantly, PG-COSH was detected from both Gram-negative (Escherichia coli) and Gram-positive (Staphyrococcus aureus) bacteria under the treatment of penicillin G, suggesting the endogenous formation of PG-COSH. Our data suggest that carbothioic S-acid β-lactams may be useful biomarkers for monitoring hydropersulfide-catalyzed inactivation of β-lactams, and hence, for exploring potent antibacterial modulators that are capable of enhancing antibacterial activity of β-lactams by inhibiting hydropersulfides formation.