Comprehensive screening of potential inhibitors from ZINC15 database for Metallo-L1 Β -Lactamase from Stenotrophomonas maltophilia via in Silico and in vitro approaches.

BACKGROUND

Antibiotic resistance caused by pathogenic microbes have become a serious issue in health field as most of the antibiotics discovered are rendered ineffective for the treatment of numerous microbial infections. Stenotrophomonas maltophilia is such a type of pathogen and the treatment of this bacterial infection is extremely difficult due to its intrinsic multi-drug resistance property. Production of β-lactamases (L1 and L2) by the organism is one of the main causes of resistance to a broad spectrum of antibiotics. β -lactamase inhibitor and β-lactam drug combination can be a promising alternative.

RESULT

In the current study, approximately 500,000 compounds from ZINC15 database were subjected to virtual High Throughput screening (vHTS). Compounds with binding energies in the range of - 8.1 kcal/mol to - 7.2 kcal/mol were shortlisted for further analysis After molecular docking and ADMET analysis, ZINC393032 (-7.3 kcal/mol) and ZINC616394 (-7.6 kcal/mol) were selected for 300 ns Molecular Dynamics (MD) simulation. Analysis of RMSD, RMSF and Hydrogen bond concluded ZINC393032 as the best compound. In vitro validation assays with the screened inhibitor on recombinant Metallo-L1 β-lactamase like enzyme inhibition (IC obtained at 22.96 µM), MIC (Minimum inhibitory concentration), checkerboard synergy assay and time kill assay showed good inhibitory property. Five different concentration combinations of the inhibitor with imipenem were tested against the bacteria and found to have bactericidal effects.

CONCLUSION

The study validates a promising compound for overcoming resistance caused by L1 β-lactamase in Stenotrophomonas maltiphilia. These results highlight the potential of combining computational and experimental approaches to develop novel therapies. The findings provide a foundation for future strategies targeting β-lactamase-mediated resistance in Stenotrophomonas maltophilia.