A new culprit in antibacterial resistance: Cysteine persulfide

Bacteria are different from animal cells in that their outer layer is covered with a rigid structure called a cell wall. β-lactam antimicrobial agents interfere with the processes that form the cell wall. This results in bacteria no longer being able to withstand their own internal pressure so they rupture and die. β-lactam antimicrobial agents are very potent because they selectively inhibit bacterial cell wall synthesis and have few side effects on hosts such as humans. These antimicrobial agents have a common structure called the β-lactam ring that is essential for inhibiting cell wall development. If this ring is degraded, the antimicrobial effect disappears.

Previous studies have reported that hydrogen sulfide (H2S), which bacteria produce during sulfur metabolism, reduces their susceptibility to antimicrobial agents leading to resistance. However, the detailed mechanism causing this are not yet understood. Researchers at Kumamoto University previously showed that the molecule cysteine persulfide, a combination of H2S and the amino acid cysteine,has an extremely potent antioxidant effect that is not found in H2S or cysteine alone.

They discovered that β-lactam antibiotics such as penicillin G, ampicillin, and meropenem (carbapenem antibiotics) rapidly lose bactericidal activity when exposed to cysteine persulfide but not with hydrogen sulfide. A detailed study of the reaction between β-lactam antimicrobial agents and cysteine persulfide revealed that the β-lactam ring, which is essential for bactericidal action, decomposes and a sulfur atom is inserted into part of the ring creating carbothioic acid.The production of carbothioic acid from a β-lactam antimicrobial agent appears to be a novel degradation metabolite.

A new culprit in antibacterial resistance: cysteine persulfide

Fig: β-lactam antimicrobial agents inside the bacteria are degraded to carbothioic acid and then discharged.

Researchers thus developed a highly sensitive analytical method to detect and quantify carbothioic acid using mass spectrometry, and then analyzed carbothioic acid production from bacteria that were exposed to β-lactam antimicrobials. They found that bacteria can absorb antimicrobial agents and use cysteine persulfide to degrade the agents into carbothioic acid which is then discharged. This is believed to be a previously undescribed inactivation and degradation mechanism of β-lactam antimicrobial agents into carbothioic acid by cysteine persulfide.

atsuhiko Ono et al, Cysteine Hydropersulfide Inactivates β-Lactam Antibiotics with Formation of Ring-Opened Carbothioic S-Acids in Bacteria, ACS Chemical Biology (2021). DOI: 10.1021/acschembio.1c00027

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