Exploring Antimicrobial Potency, ADMET, and Optimal Drug Target of a Non-ribosomal Peptide Sevadicin from Bacillus pumilus, through In Vitro Assay and Molecular Dynamics Simulation

Sajid Iqbal; Farida Begum; Mohammad Y Alfaifi; Serag Eldin I Elbehairi; Abubakar Siddique; Peter Shaw

doi:10.1007/s12602-024-10355-8

Exploring Antimicrobial Potency, ADMET, and Optimal Drug Target of a Non-ribosomal Peptide Sevadicin from Bacillus pumilus, through In Vitro Assay and Molecular Dynamics Simulation

Probiotics Antimicrob Proteins. 2024 Sep 24. doi: 10.1007/s12602-024-10355-8. Online ahead of print.

Authors

Sajid Iqbal^{1

2}, Farida Begum¹, Mohammad Y Alfaifi^{3

4}, Serag Eldin I Elbehairi^{3

4}, Abubakar Siddique⁵, Peter Shaw⁶

Affiliations

¹ Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, Zhejiang, P.R. China.
² School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, P.R. China.
³ Biology Department, Faculty of Science, King Khalid University, Abha, 9004, Saudi Arabia.
⁴ Tissue Culture and Cancer Biology Research Laboratory, King Khalid University, Abha, 9004, Saudi Arabia.
⁵ Department of Veterinary Medicine, College of Animal Sciences, Zhejiang University, Hangzhou, P.R. China.
⁶ Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, Zhejiang, P.R. China. petershaw@ojlab.ac.cn.

PMID: 39316258
DOI: 10.1007/s12602-024-10355-8

Abstract

The current study was designed to explore the biosynthetic potential of sevadicin in Bacillus pumilus species and its interaction with bacterial drug target molecules. The non-ribosomal peptide (NRP) cluster in B. pumilus SF-4 was preliminarily confirmed using PCR-based screening, and the bioactivity of strain SF-4 culture extract was assessed against a set of human pathogenic strains. The susceptibility assay showed that strain SF-4 extract had higher inhibitory concentrations (312-375 µg/mL) than ciprofloxacin. Genome mining of B. pumilus strains (n = 22) using AntiSMASH and BAGEL identified sevadicin coding biosynthetic gene cluster only in strain SF-4, constitutes of two core biosynthetic genes, three additional biosynthetic genes, two transport-related genes, and one regulatory gene. The molecular docking of sevadicin with various putative bacterial drug targets such as dihydropteroate, muramyl ligase E, topoisomerase, penicillin-binding protein, and in vitro safety analyses were conducted with detailed ADMET screening. The results showed that sevadicin makes hydrophobic interaction with MurE (PDB ID: 1E8C and 4C13) via hydrogen bonding, suggesting bacterial growth inhibition by disrupting the cell wall synthesis pathway and exhibiting a secure biosafety profile. The stability and compactness of sevadicin/MurE complexes were assessed via molecular dynamic simulation using RMSD, RMSF, and Rg. The simulation results revealed the binding stability of sevadicin/MurE complexes and indicated that the complexes can't be easily deformed. In conclusion, the current study explored the biosynthesis of sevadicin in B. pumilus for the first time and found that sevadicin inhibits bacterial growth by inhibiting cell wall synthesis via targeting the MurE enzyme and exhibits no toxicity.

Keywords: Bacillus pumilus; Antibacterial activities; Biosynthetic gene cluster; Molecular dynamic simulation; Muramyl ligase E; Sevadicin.

Grants and funding

No. OJQD2022005/Science Foundation of Oujiang Laboratory