Life Sciences & Biotechnology
Title : | Rational design, development and anti-microbial activity evaluation of a new class of inhibitors of bacterial peptidyl-tRNA hydrolase for tackling AMR |
Area of research : | Life Sciences & Biotechnology |
Focus area : | Medical Chemistry, Microbiology |
Principal Investigator : | Dr. Ashish Arora, CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow, Uttar Pradesh |
Timeline Start Year : | 2023 |
Timeline End Year : | 2026 |
Contact info : | ashish_arora@cdri.res.in |
Details
Executive Summary : | Bacterial peptidyl-tRNA hydrolase (Pth) is a crucial enzyme in the development of anti-microbial drugs. It recycles peptidyl-tRNA that are prematurely released during translation, killing bacteria due to peptidyl-tRNA accumulation and tRNA starvation. Pth's catalytic site residues are conserved across all bacterial species, making it a universal anti-bacterial target. Researchers have used structural information to design rational inhibitors for Pth, using standardized preparation of alpha-N-BODIPY-lysyl-tRNALys as a substrate for enzyme activity assays. A sensitive assay was developed using HPLC coupled with fluorescence detection. One lead compound inhibited Pth significantly, with low MIC against Gram-positive bacteria, S. aureus, and E. faecium, and equipotent activity against clinical MRSA, VRSA, and VRE strains. The Pth inhibitor exhibited low cytotoxicity and synergy with gentamicin and caused higher S. aureus biofilm mass reduction compared to vancomycin. The current proposal aims to rationally design and evaluate new Pth inhibitors with broader anti-microbial activity against all ESKAPE pathogens, lower toxicity, and better solubility. Computational tools will be employed for in silico design and screening, and the crystal structure of E. faecium Pth and K. pneumoniae Pth will be determined. Pth enzyme activity inhibition assays will be performed using Pth fluorescent substrate with HPLC coupled with fluorescence detection. The proposed work will yield potential leads for the anti-microbial drug pipeline, along with a wealth of structural information. |
Co-PI: | Dr. Sidharth Chopra, CSIR-Central Drug Research Institute (CSIR-CDRI), Lucknow, Uttar Pradesh-226031 |
Total Budget (INR): | 42,22,800 |
Organizations involved