Researchers from New York University School of Medicine have discovered that inhibiting hydrogen sulfide production in some bacteria—such as Staphylococcus aureus and Pseudomonas aeruginosa—could make them more susceptible to antibiotics.
Some bacteria have developed strategies to tolerate and survive exposure to antibiotics, a process somewhat different to antibacterial resistance, which is often due to genetic mutations. One such strategy is to slow down growth and replication by producing hydrogen sulfide.
“Bacteria appear to use controlled, self-poisoning with hydrogen sulfide to slow down their metabolism, preventing the antibiotics from using the bacteria’s energy production system to kill them,” says Evgeny Nudler, Ph.D., a professor at NYU Langone Health, and an investigator at New York University School of Medicine, who led the study.
“Interfering with the hydrogen sulfide-based defenses represents a largely unexplored alternative to the traditional antibiotic discovery.”
Hydrogen sulfide is produced as a protective strategy by a number of different bacterial species including species that are also becoming more and more resistant to antibiotics such as gram-positive S. aureus and gram-negative P. aeruginosa, which are responsible for many hospital-acquired infections.
Both S. aureus and P. aeruginosa rely on an enzyme called cystathionine γ-lyase (CSE) to produce protective hydrogen sulfide in response to antibiotic exposure. While inhibitors of this enzyme are available, their efficacy is not high and they have a high chance of causing side effects if given to humans.
To search for more effective and less toxic inhibitors, Nudler and colleagues studied the X-ray structure of CSE from S. aureus and used it to screen millions of potential inhibitors.
As reported in the journal Science, they found three possible candidate drugs which effectively inhibited CSE activity. The compounds also blocked hydrogen sulfide production and strengthened the effect of available antibiotics both in the lab and in a mouse model.
When tested against S. aureus and P. aeruginosa, the researchers found that the inhibitor drugs reduced the number of tolerant bacteria significantly and also reduced biofilm formation. Importantly, no obvious signs of toxicity were associated with the most effective inhibitor when it was tested in human cells and in the mouse model.
This approach is still at the early stages and needs to be validated in clinical trials, but the team thinks this approach could be used in several ways to overcome antibacterial tolerance or resistance. For example, if these inhibitors are approved, it may be possible to reduce antibiotic dose and help minimize side effects if given in combination with a hydrogen sulfide production inhibitor.
“The combined trends toward resistant infections and fewer new antimicrobials are projected to kill 10 million people annually by the year 2050,” says Nudler.
“New approaches are urgently needed to prevent this, and our study suggests that suppressing bacterial hydrogen sulfide would make different antibiotics more potent.”
