Researchers discover essential role of hydrogen sulfide in bacteria’s ability to survive antibiotics
TThe hydrogen sulfide signaling molecule (H2S) plays a critical role in antibiotic tolerance, the innate ability of bacteria to survive normally lethal levels of antibiotics, according to a new study.
To be published on June 11 in the journal Science, the study revolves around tolerance, in which bacteria in general have evolved to use common defense systems to resist antibiotics. Tolerance differs from antibiotic resistance, where a species acquires a genetic change that helps it resist treatment.
In a defense mechanism, the tolerant bacteria, also called “persistent”, stop multiplying (proliferate), reducing their energy consumption (metabolism) to survive the antibiotic treatment, but resuming their growth at the end of the treatment. Persists are particularly abundant in biofilms, bacterial colonies that live in resistant polymeric matrices, which further prevents their eradication.
“The combined trends towards resistant infections and fewer new antimicrobials are expected to kill 10 million people per year by 2050,” says corresponding study author Evgeny A. Nudler, PhD, professor of biochemistry Julie Wilson Anderson at department of biochemistry and molecular biology. Pharmacology at NYU Langone, and researcher at Howard Hughes Medical Institute. “New approaches are urgently needed to prevent this, and our study suggests that removing the H2S would make different antibiotics more potent.
In their previous work, the NYU Langone research team showed that H2The production of S is deployed against antibiotics by a wide variety of bacterial species, including two pathogens increasingly resistant to antibiotics prevalent in nosocomial infections: Staphylococcus aureus and Pseudomonas aeruginosa. S. aureus is Gram positive, while Pseudomonas aeruginosa is gram-negative, with the different organizations of their outer layers showing that H2The production of S protects pathogens throughout the bacterial kingdom.
Remarkably, the research team found that both species rely on the same enzyme, cystathionine -lyase (CSE), for most of H2manufacture S. Blocking its action would then represent a means of suppressing an important defense against antibiotics, but the available CSE inhibitors have a low potency against bacterial CSE and a high probability of causing side effects in human tissues, explains Dr. Nudler.
To find better inhibitors, the research team obtained an X-ray structure of S. aureus CSE and used it to “virtually” examine millions of drug-like compounds for those with the right form and properties to block the action of the enzyme without side effects. The team selected major compounds, NL1, NL2 and NL3, which inhibited the bacterial CSE, blocked H2S production by both S. aureus and P. aeruginosa, and enhanced the effect of bactericidal antibiotics of different classes. In addition, NL1 increased the potency of the antibiotic effect in mouse models of S. aureus and P. aeruginosa infection.
Unexpectedly, further testing revealed that the NL compounds significantly reduced persistence and suppressed biofilm formation in both pathogens.
How exactly H2S contributes to tolerance remains to be established, but there are some clues.
“The bacteria appear to use controlled self-poisoning with H2S to slow their metabolism, preventing antibiotics from using the bacteria’s energy-producing system to kill them, ”says Dr. Nudler. “Interfere with the H2S-based defenses represent a largely unexplored alternative to the traditional discovery of antibiotics. Our results suggest that a new type of small molecule potentiator may enhance the effect of major classes of clinically important antibiotics.
The authors note several opportunities to design conceptually new antimicrobial therapies by combining H2Potentiators S-blockers with antibiotics. Such combinations may have better efficacy against bacterial biofilms. Other potential applications include overcoming resistance to mid-level antibiotics, reducing antibiotic dose and associated toxicity while maintaining efficacy, and enhancing antibacterial (bactericidal) effect at the same dose of antibiotic.
Together with Dr Nudler, the study was led by lead authors Konstantin Shatalin and Ashok Nuthanakanti from the Department of Biochemistry and Molecular Pharmacology. The authors were also Abhishek Kaushik, Alla Peselis, Ilya Shamovsky, Bibhusita Pani, Mirna Lechpammer, Nikita Vasiliev, Elena Shatalina and Alexander Serganov at NYU Langone, as well as Dmitry Shishov and Peter Fedichev of Gero LLC, Moscow, Russia; Dmitri Rebatchouk of Ellyris LLC in Union, New Jersey; and Alexander Mironov from the Engelhardt Institute for Molecular Biology, Russian Academy of Sciences in Moscow. The study was funded by the Blavatnik Family Foundation, the US Department of Defense, and the Howard Hughes Medical Institute.