Volume 17, Issue 40, July - December, 2023

Inhibition of New Delhi Metallo-β-lactamase 1 from Klebsiella pneumoniae by an L-aspartic acid derivative

Destiny Morris M¹, Jhawn Saul G¹, Sarah Faubion C¹, Kaliana Lee C¹, Sung-Kun Kim^1♦

¹Department of Natural Sciences, Northeastern State University, Broken Arrow, Oklahoma 74014, The United States of America

^♦Corresponding author
Department of Natural Sciences, Northeastern State University, Broken Arrow, Oklahoma 74014, USA

ABSTRACT

The overuse of β-lactam antibiotics has caused drug-resistant bacteria, including NDM-1, a Metallo-β-lactamase that renders inhibitors ineffective. NDM-1 is found in Klebsiella pneumoniae, causing worldwide resistant infections. Developing an NDM-1 inhibitor is vital for managing bacterial resistance and public health. This study investigated L-aspartic acid β-benzyl ester 7-amido-4-methylcoumarin (Asp (OBzl)-AMC) as a potential NDM-1 inhibitor through in vitro and in silico evaluations. Enzyme kinetics indicated competitive inhibition, with an IC50 value of 30.4 ± 5.0 μM and a Ki value of 11.4 ± 1.2 μM. Molecular docking showed Asp (OBzl)-AMC forming hydrogen bonds with NDM-1's active site residues. Asp (OBzl)-AMC displayed favorable ADME properties, making it a promising drug candidate. The study demonstrates that Asp (OBzl)-AMC effectively binds to NDM-1 and inhibits its activity. The compound's attachment to the naphthalene ring is crucial for protecting β-lactam antibiotics from NDM-1 damage. These findings suggest that Asp (OBzl)-AMC holds potential as an NDM-1 inhibitor to combat bacterial resistance and maintain public health.

Keywords: Metallo-beta-lactamase, enzyme, inhibition, kinetics, molecular dynamics

Drug Discovery, 2023, 17(40), e28dd1945

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DOI: https://doi.org/10.54905/disssi.v17i40.e28dd1945

Published: 12 August 2023