Author(s) :

Jayden Cho.

Volume/Issue :

Abstract :

Carbapenemase-producing bacteria are a major global health concern because they can hydrolyze a broad range of β-lactam antibiotics, including carbapenems that are often used as last-resort treatments. Among these enzymes, New Delhi metallo-β-lactamases (NDMs) are particularly problematic due to their broad substrate spectrum, rapid global dissemination, and the limited availability of clinically effective inhibitors. In this study, a structure-based docking analysis of selected fungal metabolites against NDM-family metallo-β-lactamases was performed. Seventeen fungal metabolites were initially screened, and eight compounds were selected for docking against eight experimentally resolved NDMfamily structures using CB-Dock2. The resulting complexes were further examined and visualized using UCSF Chimera. Protein-ligand interactions were analyzed using PLIP and electrostatic surface mapping. An empirical cutoff (Vina score ≤ −8.0 kcal/mol) was used as a practical prioritization criterion rather than as a predictor of inhibitory activity. Pulvinic acid, Pseurotin A, Hispidin, and Scytalone were prioritized for further analysis. Hispidin and Scytalone tended to localize near catalytic regions, whereas Pulvinic acid and Pseurotin A more frequently occupied adjacent or substrate-entry regions. Reference β-lactamase inhibitors were included to provide structural context for docking interpretation. These ligands localized within predicted binding regions and provided a basis for comparison with fungal metabolites. None of the compounds demonstrated direct Zn²⁺ coordination, suggesting that classical zinc-chelation-based inhibition is unlikely. ADMET predictions indicated that Hispidin and Scytalone possess relatively favorable drug-like properties, whereas Pulvinic acid and Pseurotin A may serve as initial scaffolds for further optimization. Overall, this study highlights fungal natural products as structurally diverse compounds that may serve as useful starting points for exploring ligand interactions with NDM-family metallo-β-lactamases and generating hypotheses for future inhibitor development.