Bacterial hydrogen sulphide biogenesis contributes to antibiotic resistance

 Souradip Mallick, National Institute of Technology, Rourkela

Growing antimicrobial resistance is one of the major threats to the world.  It has been estimated that over 10 million deaths each year by 2050 if no action is taken. The World Health Organization (WHO) also apprises that by 2030, drug-resistant diseases could force up to 24 million people into extreme poverty and cause catastrophic damage to the world economy. In this scenario, the discovery of survival of the bacteria in presence of antibiotics by producing bacterial hydrogen sulphide (H₂S), illuminates the path for a brighter future.

Hydrogen sulphide (H₂S) is one of the essential factors that enhance the bacteria to survive in lethal levels of antibiotics normally. Moreover, hydrogen sulfide protects bacteria against the toxic effects of oxidative stress. The production of the signaling molecule hydrogen sulfide (H₂S) was studied in different bacterial species such as Staphylococcus aureus and Pseudomonas aeruginosa. These two bacteria are hospital-borne antibiotic-resistant pathogens.  In this study, it has been observed that the production of H₂S protects pathogen across the bacterial kingdom.

Staphylococcus aureus, gram-positive bacteria, and Pseudomonas aeruginosa, gram-negative bacteria depend primarily on cystathionine γ-lyase (CSE) enzyme for the production of H₂S. The bacteria can protect themselves from the lethal level of antibiotic stress by blocking the action of cystathionine γ-lyase (CSE). These CSE inhibitors have high potency against the human tissue but have low potency against bacterial CSE. The production of H₂S decreases the metabolism of bacteria and prevents the antibiotics from utilizing the bacteria’s energy production system to kill them.

The improvement of CSE inhibitors in terms of shape and properties is necessary to rightly fit to block the active site of the enzyme and so that it does not have any side effects. For this analysis, the X-ray structure of S. aureus CSE and P. aeruginosa CSE was analyzed. It has been observed that the compounds NL1, NL2, and NL3 have the potential ability to inhibit the bacterial CSE, thereby block the production of bacterial hydrogen sulphide (H₂S) by both S. aureus and P. aeruginosa and strengthen the effect of bactericidal antibiotics from different classes. Moreover, NL1 can also increase the effect of antibiotic stress in mouse models of S. aureus and P. aeruginosa infection. NL compounds can also diminish persisters, and suppressed the formation of biofilm in both pathogens, but still, now the exact mechanism of suppression of biofilm formation by NL compounds are not clear. 

The H2S based defenses can act as an alternative strategy for the discovery of antibiotics. Furthermore, potentiator molecules can increase the effect of major classes of clinically important antibiotics.

Thus there are several alternatives are there for designing novel antimicrobial therapeutics by combining H₂S-blocking potentiators with antibiotics. Such type combinations with antibiotics may have better efficacy against bacterial biofilms. Other potential applications can also include overcoming intermediate-level antibiotic resistance; reducing the antibiotic dose and related toxicity while maintaining efficacy, and enhancing the bacteria-killing (bactericidal) effect at the same antibiotic dose.

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Source:  

1. Shatalin K.,  Nuthanakanti A.,  Kaushik A.,  Shishov D.,  Peselis A.,  Shamovsky I.,  Pani B.,  Lechpammer M.,  Vasilyev N.,  Shatalina E.,  Rebatchouk D.,  Mironov A.,  Fedichev P.,  Serganov A.,  Nudler E. (2021). Inhibitors of bacterial H2S biogenesis targeting antibiotic resistance and tolerance. Science vol. 372 no. 6547 1169-1175.
   https://doi.org/10.1126/science.abd8377.
2. NYU Langone Health. Hydrogen sulfide critical to innate ability of bacteria to survive antibiotics. https://phys.org/news/2021-06-hydrogen-sulfide-critical-innate-ability.html.

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