Life Sciences & Biotechnology
Title : | Chemical modulation of bacterial ATP synthase to identify novel chemical scaffolds targeting active and latent Mycobacterium tuberculosis |
Area of research : | Life Sciences & Biotechnology |
Principal Investigator : | Dr. Rashmi Sharma, CSIR-Indian Institute Of Integrative Medicine (CSIR–IIIM), Jammu and Kashmir |
Timeline Start Year : | 2022 |
Timeline End Year : | 2024 |
Contact info : | rashmi.sharma.09@iiim.res.in |
Equipments : | Bio safety cabinet
Absorbance Plate Reader
Compound Microscope
CO2 Incubator |
Details
Executive Summary : | The emergence of drug resistance in tuberculosis (TB) has been crippling the public health system for decades with the advent of Multi drug resistance (MDR) and extensively drug resistant (XDR) TB strains. Mycobacterium tuberculosis (Mtb), the causative agent of TB, has exceptional resilience to survive within the host, alternating between active (replicating) and latent (non replicating) states; escaping the immune system defences at the same time. The FDA approval of Bedaquiline for the treatment against MDR cases brought energy metabolism pathway to the forefront whereby exposing the enzymes of electron transport chain (ETC) for exploitation for drug discovery against TB. Targeting ETC chain enzymes would target the heterogenous bacterial population in the host as oxidative phosphorylation is essential for both the active and latent forms of Mtb, making ETC enzymes as attractive targets for anti-TB drug programs. One such ETC enzyme is ATP synthase. There is a scarcity of novel chemical scaffolds targeting ATP synthase with ongoing research focus on derivatives of bedaquiline rather than exploring novel hits against the target. In this project, we aim to widen the chemical space for the pharmacologically validated drug target, ATP synthase. The proposed project aims at identification of novel chemical scaffolds against ATP synthase to target active and latent Mtb. We have identified potent anti-TB hits from a phenotypic screen of a small molecule chemical library of 10,000 compounds that are proposed to be tested for ATP synthase inhibition using luciferin based enzymatic assay in mycobacterial membrane vesicles and whole cell Mtb lysate. Experimentations involving whole genome sequencing and molecular docking would be utilized for gaining mechanistic insights. As identified hits, would be investigated using both ex vivo high content and in vivo studies against MDR and non replicating persister strains. The proposed project addresses the need of exploiting diverse chemical libraries for identification of novel potent hits targeting ATP synthase. The expected deliverable of the project is several novel chemical scaffolds that will serve as starting points for iterative medicinal chemistry effort that may lead to novel series of anti-TB agents effective against MDR and latent TB. |
Total Budget (INR): | 29,24,330 |
Organizations involved