Bacterial Metabolite-Derived NDM-1 Inhibitors: A Computational Strategy to Overcome β-Lactam Resistance

Area of Science:

• Microbiology
• Medicinal Chemistry
• Computational Biology

Background:

• New Delhi metallo-β-lactamase-1 (NDM-1) is a significant threat to antibiotic efficacy.
• There is an urgent need for novel inhibitors to combat NDM-1-mediated antibiotic resistance.

Purpose of the Study:

• To identify bacterial-derived natural metabolites as potential inhibitors of New Delhi metallo-β-lactamase-1 (NDM-1).
• To evaluate the drug-likeness, binding affinity, and inhibitory potential of screened metabolites.

Main Methods:

• Screening of 300 bacterial secondary metabolites using induced-fit docking against NDM-1 active site residues.
• Analysis of binding affinities, drug-likeness criteria, molecular dynamics simulations, and pharmacophore modeling for top candidates.
• Evaluation of safety, bioactivity, and synthetic feasibility of identified hits.

Main Results:

• 21 out of 300 metabolites exhibited stronger binding affinities than meropenem and met drug-likeness criteria.
• Top candidates, including tumonoic acid H and vitroprocine C, formed crucial interactions with NDM-1 catalytic residues and Zn2+ ions.
• Molecular dynamics and pharmacophore modeling confirmed the stability and key interaction features of the leading inhibitors.

Conclusions:

• Bacterial natural metabolites represent a promising source for developing novel NDM-1 inhibitors.
• The identified compounds warrant further experimental investigation for their therapeutic potential against NDM-1-producing bacteria.
• This study provides a computational foundation for combating antibiotic resistance through natural product drug discovery.