Molecular docking and pharmacological profiling of hot spring fungal compounds against Klebsiella pneumoniae Β-lactamases

The rise of multidrug-resistant Klebsiella pneumoniae, particularly due to the production of β-lactamases, poses a serious risk to the public's health by compromising the efficacy of β-lactam antibiotics. This study explores the potential of three fungal-derived metabolites as β-lactamase inhibitors through in silico and molecular docking analysis. The compounds were evaluated against three clinically relevant β-lactamase enzymes (blaKPC-2, blaCTXM-14, and blaTEM-52), and their binding affinity, pharmacokinetics, and toxicity profiles were assessed using computational approaches. Molecular docking results revealed that 2,2,4,4-Tetramethyl-6-(3-methylbutanoyl) cyclohexane-1,3,5-trione (Compound 3) exhibited the strongest binding affinity across all three β-lactamases, forming multiple hydrogen bonds and hydrophobic interactions with the key active site residues. Comparative analysis with Avibactam, a clinically approved β-lactamase inhibitor, indicated similar or superior docking scores, suggesting potential inhibitory activity. Pharmacokinetic and drug-likeness evaluations confirmed that all three compounds adhered to Lipinski’s Rule of Five, with Compound 3 displaying optimal lipophilicity, solubility, and oral bioavailability. Toxicity predictions indicated low mutagenic, hepatotoxic, and cardiotoxic risks, further supporting the therapeutic potential of the tested compounds. These findings suggest that Compound 3 represents a promising lead for further development as a β-lactamase inhibitor, potentially aiding in the fight against antibiotic resistance. However, molecular dynamics simulations and in vitro enzyme inhibition assays are required to confirm its stability and efficacy in biological systems. The study underscores the value of natural product-based drug discovery in identifying novel antimicrobial agents from fungal metabolites.