A new culprit in antibacterial resistance: Cysteine persulfide

Date:
June 9, 2021
Source:
Kumamoto University
Summary:
Scientists have developed a new, highly sensitive analytical
method that can detect degraded beta-lactam antibacterial agents
used in the treatment of bacterial infections. With this method,
researchers found that reactive sulfur species produced by bacteria
degrade and inactivate beta-lactam antibiotics.



FULL STORY ==========================================================================
A joint research project based in Kumamoto University, Japan has
developed a new, highly sensitive analytical method that can detect
degraded b-lactam antibacterial agents used in the treatment of bacterial infections. With this method, researchers found that reactive sulfur
species produced by bacteria degrade and inactivate b-lactam antibiotics.


========================================================================== Bacteria are different from animal cells in that their outer layer is
covered with a rigid structure called a cell wall. b-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. b-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 b- 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.

In this study, researchers examined how this reactive sulfur species is involved in the acquisition of resistance to b-lactam antibiotics. They discovered that b-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 b-lactam antimicrobial agents and cysteine persulfide revealed that the b-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 b-lactam antimicrobial agent appears to be a novel degradation metabolite.

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 b-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 b-lactam antimicrobial agents
into carbothioic acid by cysteine persulfide.

"Our newly developed analytical method makes it possible to
quantify the amount of carbothioic acid discharged from bacteria
with high sensitivity," said Professor Tomohiro Sawa, who led the
study. "We believe it will be possible to screen for compounds
that inhibit bacterial synthesis of cysteine persulfide by using
carbothioic acid as a biomarker. Such a cysteine persulfide
synthesis inhibitor in combination with b-lactam antibiotics is
expected to inhibit antibiotic degradation and result in successful
treatments with a lower concentration of b-lactam antibiotics. This
should also help to reduce the emergence of new resistant bacteria." ========================================================================== Story Source: Materials provided by Kumamoto_University. Note: Content
may be edited for style and length.


========================================================================== Journal Reference:
1. Katsuhiko Ono, Yusuke Kitamura, Tianli Zhang, Hiroyasu Tsutsuki,
Azizur
Rahman, Toshihiro Ihara, Takaaki Akaike, Tomohiro Sawa. Cysteine
Hydropersulfide Inactivates b-Lactam Antibiotics with Formation of
Ring- Opened Carbothioic S-Acids in Bacteria. ACS Chemical Biology,
2021; 16 (4): 731 DOI: 10.1021/acschembio.1c00027 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/06/210609115516.htm

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