Microbiology: Current Research

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Abstract - Microbiology: Current Research (2021) Volume 0, Issue 0

Designing potential inhibitors against NDM-1 type metallo-?-lactamases: to overcome antimicrobial effect

 NDM-1 is the most prevalent types of metallo-?-lactamases, hydrolyse most of the antibiotics of ?-lactam group which may lead to multiple-antibiotic resistance in bacteria. A few inhibitors have been identified against  NDM-1 or other class of metallo-?-lactamases but their efficacies are in question. Hence,  we initiated to adopt strategies to identify  novel anti-?-lactamase agents with specific mechanisms of action which are utmost need of society. In this study, we have reported the discovery of novel non-?-lactam inhibitors against NDM-1 by multi-step virtual screening approach. The potential for virtually screened drugs was estimated through in vitro cell assays. Five compounds were finally identified and procured for evaluation  and  experimentally testing for their efficacies to inhibit NDM-1 producing bacterial cells, in vitro. The kinetic parameters were evaluated. The dissociation constants (Kd), association constant (Ka), stoichiometry (n) and binding energies (ΔG) of compounds with the respective targets were determined using isothermal titration calorimetry (ITC). Molecular dynamic simulation carried out for 50 ns revealed that these complexes were quite stable throughout the simulation with relative RMSD in acceptable range. Moreover, Microbiological and kinetic studies further confirmed high efficacies of these inhibitors by reducing the minimum inhibitory concentration (MIC) and catalysis of antibiotics by ?-lactamases in the presence of inhibitors. Therefore, we strongly conclude that these potential inhibitors may be used as lead molecule for future drug candidate after validation in vivo settings. 

 

Author(s): Asad U Khan

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