Development of novel Staphylococcus aureus ß-Lactamase Inhibitor through Mb-Isoster and Glide Docking Software
Keywords:
Staphylococcus aureus, β-lactamase, Docking Molecular, BioisosterismoAbstract
Staphylococcus aureus is an opportunistic bacterium that causes diseases in immunocompromised
individuals and is among the pathogens responsible for hospital-acquired infections. Antibiotic-resistant strains
like MRSA and VRSA have become a growing concern over the years. One of their mechanisms of antibiotic
resistance is the production of inactivating enzymes called class A β-lactamases. In this study, we aimed to find a
new drug capable of binding to the S. aureus β-lactamase enzyme and inhibit its activity, making multidrugresistant S. aureus susceptible to β-lactam antibiotics again. We targeted the three-dimensional structure of S.
aureus PC-1 β-lactamase, solved by X-ray crystallography at 2.0 Å resolution. We performed molecular docking
using Schrödinger Suite’s Glide software to screen a library of 228 potential inhibitors, derived from clavulanic
acid by bioisosteric replacement through MB-Isoster software. We discovered 5 new compounds that bind more
strongly to S. aureus β-lactamase than clavulanic acid, a known inhibitor. We also evaluated their
pharmacokinetic properties using Schrödinger Suite’s QikProp software and found one ligand with a satisfactory
Percent Human Oral Absorption of 82.976%. Our study demonstrates the potential of bioisosteric replacement as
a strategy for drug discovery. Future work will test the efficacy and safety of our inhibitors in vivo.
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