Blocking a hydrogen sulfide defense mechanism appears to make bacteria more susceptible to antibiotics – a finding that could offer a new way to combat antimicrobial resistance.

Drug-resistant bacteria, called persisters, are a growing global health crisis. By the middle of this century, scientists predict that antibiotic resistance will cause 10 million deaths annually. For this reason, many researchers are working to find new antibacterial agents and ways to improve the effectiveness of existing drugs.

Now a team led by medical researcher Evgeny Nudler from New York University (NYU) has discovered a new way to weaken bacterial resistance to existing treatments. The method is based on blocking a common bacterial defense mechanism with hydrogen sulfide (H.2S) production.

“Bacteria seem to use controlled self-poisoning with H.2S to slow their metabolism down and stop the antibiotics from using the bacteria ‘energy production system to kill them, ”Nudler told the NYU Langone website.

Nudler’s team identified a protein called cystathionine γ-lyase (CSE), which plays a key role in hydrogen sulfide production in two common drug-tolerant bacteria. After obtaining X-ray structures from CSE, researchers used computer tools to search more than three million small molecules looking for compounds that could bind to the protein and prevent it from functioning.

An image showing a model of an enzymatic binding pocket, shown as blue, red, and green blobs, with a rod-shaped molecular model slit in the middle.

Based on the screening results, the group evaluated the ability of dozens of compounds to prevent the formation of hydrogen sulfide in enzymatic assays. The three most promising candidates – all related compounds based on a substituted indole structure – were then tested in both test tube and mouse studies Staphylococcus aureus and Pseudomonas aeruginosa. These common persistence are two of the most common causes of hospital-acquired infections. The experiments showed that by blocking the hydrogen sulfide defense mechanism, the small molecules could actually increase the effectiveness of several antibiotics, including a type of penicillin, against the bacteria.

Medicinal chemist Miraz Rahman of Kings College London, UK, explains that finding ways to modify drug resistance in bacteria can be a temporary solution – extend the life of existing antibiotics while scientists continue to search for new classes of antibacterial agents. He says the discovery of the CSE protein as a drug-grade target “is an important new finding” that “opens up new opportunities to develop combination therapies for chronic diseases such as cystic fibrosis, where the persistence population is particularly problematic”.

“This is an early and encouraging finding against a limited number of mainly laboratory-adapted strains,” notes Rahman. “The strategy has yet to be validated against relevant clinical strains in appropriate disease models in order to assess the suitability of this target for overcoming resistance.”

However, he believes the study “lays the groundwork for developing combination therapies that target the CSE protein that may one day help overcome antimicrobial resistance.”

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