Inhibition of Mycobacterium tuberculosis β-Lactamase BlaC with Natural Products: An Integrated Computational Study
Sandra Sreekumar, Bhagya Jyothi J L, Liji Selvanose, Subhash Chandra Pani, Immanuel DhanasinghIntroduction:
Tuberculosis (TB), caused by Mycobacterium tuberculosis, remains the second leading cause of infectious disease-related mortality worldwide. Resistance to β-lactam antibiotics is largely attributed to the chromosomally encoded BlaC β-lactamase, which hydrolyzes commonly used β-lactam drugs. Although inhibitors such as clavulanate are clinically effective, they may promote the emergence of resistance mechanisms. Therefore, there is an emerging need to identify novel inhibitors that lack a β-lactam scaffold to overcome limitations of existing β-lactam-based inhibitors. This study aims to identify potential natural product inhibitors lacking a β-lactam scaffold against BlaC using an integrated computational approach.
Methods:
A total of 10,000 natural compounds from the Natural Products Atlas (NPAtlas), a microbial natural products database from PubChem, and the ZINC database were screened against BlaC using molecular docking-based virtual screening. The top-ranked compounds were further subjected to site-specific docking and ADMET profiling. Three lead compounds: NPA001729 (Lecanorafuran A), NPA011913 (Tryptoquivaline K), and NPA002942 (Deacetylisowortmin A) were selected for triplicate 100 ns molecular dynamics (MD) simulations. The stability of the protein-ligand complexes was assessed using RMSD, RMSF, radius of gyration (Rg), solvent-accessible surface area (SASA), principal component analysis (PCA), and free energy landscape (FEL) analyses. Binding free energies were subsequently estimated using MM-PBSA calculations.
Results:
Virtual screening identified the top ten compounds with binding energies ranging from -10.6 to -9.7 kcal/mol, outperforming the reference ligand Doripenem (-7.35 kcal/mol). Among the selected leads, Lecanorafuran A demonstrated the most stable binding interactions, with consistent structural stability and favorable conformational behavior. MM-PBSA calculations further confirmed the strong binding affinity of Lecanorafuran A toward BlaC, indicating its promising inhibitory potential.
Discussion:
Natural products lacking a β-lactam scaffold may circumvent resistance mechanisms associated with conventional β-lactam-based inhibitors. The superior computational performance of Lecanorafuran A highlights the therapeutic potential of lichen-derived dibenzofuran compounds as promising scaffolds for novel anti-TB drug development.
Conclusion:
This study identified Lecanorafuran A as a promising natural BlaC inhibitor through integrated computational screening and simulation approaches. These results support its further experimental validation as a potential therapeutic candidate against multidrug-resistant TB.