Novel Inhibitors Targeting Class B1 Metallo-β-Lactamases in Carbapenem-Resistant Acinetobacter baumannii.

Area of Science:

• Computational chemistry and drug discovery
• Molecular biology and infectious diseases

Background:

• Multidrug resistance (MDR) in Acinetobacter baumannii is a critical threat, driven by carbapenem-hydrolyzing metallo-beta-lactamases (MBLs) like IMP, VIM, and NDM.
• The efficacy of carbapenem antibiotics is severely compromised, necessitating the development of novel therapeutic strategies.

Purpose of the Study:

• To identify novel inhibitors targeting Class B1 MBLs (IMP-2, VIM-1, NDM-1) using structure-based virtual screening.
• To evaluate the drug-likeness, binding potential, and stability of identified lead compounds.

Main Methods:

• Extensive virtual screening of 66,734 compounds from diverse chemical libraries (ENAMINE, CMNPD, ASINEX, ChemDiv).
• High-throughput docking, ADME/T filtering, and molecular dynamics (MD) simulations using Schrödinger and GROMACS.
• Binding free energy calculations (MM-GBSA) and essential dynamics analysis to validate inhibitor stability and efficiency.

Main Results:

• Marine-derived CMNPD molecules exhibited superior drug-likeness and binding potential.
• Three lead inhibitors (CMNPD29415 for IMP-2, CMNPD8077 for VIM-1, BDE_30700625 for NDM-1) showed stable interactions with catalytic residues.
• MD simulations confirmed robust dynamic behavior, low RMSD fluctuations, and reduced active-site mobility for the lead compounds.

Conclusions:

• Structurally unique marine metabolites represent promising scaffolds for developing inhibitors against Class B1 MBLs.
• The identified lead compounds demonstrate significant potential for combating carbapenem resistance in Acinetobacter baumannii.
• Further experimental validation is required to assess the translational applicability of these marine-derived inhibitors.