Novel mechanism to develop a new class of drug that targets multidrug-resistant bacteria


11 May 2017

Novel mechanism to develop a new class of drug that targets multidrug-resistant bacteria

 

Novel mechanism to develop a new class of drug that targets multidrug-resistant bacteria

By Dr Amit Singh, Senior Fellow

IISc, Bangalore

In our recently published work in Chemical Sciences, we used chemical-biological approaches to identify the role of hydrogen sulfide (H2S) gas produced by bacteria in driving multi-drug resistance. H2S gas is generally considered as a metabolic byproduct with no biological consequence, however, our study not only revealed that multi-drug resistant uropathogenic strains isolated from patients produce much more H2S, but also showed that inhibition of H2S production reversed drug-resistance to a significant level. In collaboration with Harinath Chakrapani, IISER, Pune, we have synthesized small molecules H2S donors which selectively releases H2S inside bacteria.

By modulating intrabacterial levels of H2S, we demonstrated that H2S protects bacteria from antibiotics. Mechanistically, we showed H2S mitigates oxidative stress caused by antibiotics, thereby promoting resistance to diverse clinically-relevant drugs. We identified that H2S is able to show its protective effect by activating alternate respiration in E.coli coordinated by cytochrome bd oxidase (cydb). This protein not only participates in respiration but also detoxify any harmful reactive oxygen species produced by antibiotics. Altogether, our study revealed that by inhibiting H2S production and cytochrome bd oxidase in bacteria, we can effectively kill drug resistant pathogens. Future studies will be aimed to generate novel compounds which blunts H2S production and cydb-mediated alternate respiration to target antimicrobial resistance.

“On Demand” Redox Buffering by H2S Contributes to Antibiotic Resistance Revealed by a Bacteria-Specific H2S Donor
Prashant Shukla,  Vinayak S Khodade,  Mallojjala SharathChandra,  Preeti Chauhan,  Saurabh Mishra,  Shivakumara Siddaramappa,  Eswarappa Pradeep Bulagonda,  Amit Singh  and  Harinath Chakrapani. Chemical Science, April 2017