Unraveling the mechanisms of spinigerin: A promising antimicrobial peptide against antibiotic resistance through molecular dynamics simulations.

The rise of infectious diseases driven by antibiotic resistance has become a critical global concern, prompting the search for alternative therapeutic strategies. Among these, antimicrobial peptides (AMPs) have emerged as promising candidates. Spinigerin, a potent AMP, has demonstrated significant antibacterial and antifungal activity. Its mechanism involves disrupting microbial cell membranes by forming transmembrane pores that induce cell lysis. However, the precise mechanisms underlying pore formation remain poorly understood. To explore spinigerin's pore-forming potential, a comprehensive study was conducted using five different membrane models. A combination of coarse-grained (CG) and all-atom (AA) molecular dynamics simulations, along with umbrella sampling, was employed to elucidate the interactions between spinigerin and the membrane models. The results revealed that the peptide induces notable structural changes in the anionic and hybrid membranes, such as increased curvature, lipid reorganization, and altered membrane thickness. In contrast, spinigerin maintains stability in zwitterionic membranes with minimal disruption. Additionally, pore dimension analysis indicated that the initial stage of pore formation was more feasible and stable in the anionic and zwitterionic-anionic membrane models compared to the zwitterionic membrane. These findings underscore the critical role of lipid composition in determining the efficacy and mechanism of action of AMPs like spinigerin. Outstandingly, spinigerin's selective ability to target bacterial membranes while sparing host cells highlights its strong potential as a therapeutic agent.