Sanguinarine induces the unfolding of Staphylococcus aureus-derived FtsZ and reduces the conformational flexibility necessary for assembly.

Methicillin-resistant Staphylococcus aureus (MRSA) represents a serious global health challenge due to its resistance to multiple antibiotics, especially β-lactams, which limits treatment options and results in high morbidity and mortality rates. Thus, there is an urgent need for effective antibacterial agents and a deeper understanding of their mechanisms of action to combat the increasingly severe threat of bacterial resistance. In this study we have performed microbiological, molecular biology experiments and molecular dynamics simulations to investigate the antimicrobial efficacy of the sanguinarine (SAN) against MRSA and its conformational modulation of the Filamentous temperature-sensitive mutant Z (FtsZ). Our findings indicate that SAN exhibits promising anti-MRSA activity and spontaneously targets the nucleoid binding domain (NBD) of SaFtsZ to inhibit bacterial division. Additionally, SAN induces multiple single-nucleotide polymorphisms (SNPs) in the SaFtsZ coding gene, including Asp187, and site-directed mutagenesis confirms the critical role of this residue in binding. Notably, SAN causes the unfolding of SaFtsZ, significantly reducing the structural flexibility required for polymerization and triggering conformational changes. At higher dimensions, SAN disrupts protofilaments assembly, ultimately inhibiting septum formation and division. These findings provide multidimensional, high-resolution insights into the interaction between SAN and SaFtsZ, offering effective strategies for the prevention and eradication of MRSA.