Antimicrobial activities of quaternary phosphonium-type small molecular antibacterial materials against methicillin-resistant <i>Staphylococcus aureus</i>

Methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) has become a significant public health concern due to its resistance to most antibiotics and its ability to form persistent biofilms, complicating treatment strategies. The need for new and effective antibacterial agents that can overcome these challenges is urgent. In this study, we address this issue by synthesizing and evaluating five quaternary phosphonium-type small molecular antibacterial agents ([MTPP]·I, [ETPP]·I, [ITPP]·I, [BTPP]·I, and [PTPP]·I) against MRSA. Our findings show that as the alkyl chain length of the phosphonium compounds increases, their antibacterial activity significantly improves, with [PTPP]·I exhibiting the highest efficacy. This compound demonstrated a minimum inhibitory concentration (MIC) of 16 µg/mL and was able to sustain bacterial growth inhibition for up to 36 h at the MIC. The study uniquely reveals a positive correlation between alkyl chain length and antibacterial potency, offering a novel insight into the mechanism of quaternary phosphonium salts. Mechanistic studies, including protein leakage assays, reactive oxygen species (ROS) measurement, and scanning electron microscopy (SEM), confirmed that [PTPP]·I targets MRSA by electrostatic interactions with the bacterial membrane, disrupting membrane integrity, inducing content leakage, and triggering ROS burst, ultimately leading to bacterial cell death. Additionally, [PTPP]·I demonstrated a 96.6% inhibition rate against MRSA biofilms and low cytotoxicity (cell viability >97%). This research not only presents a promising candidate for MRSA drug development but also contributes a comprehensive structure-activity-mechanism approach to combat bacterial resistance and biofilm-associated infections. IMPORTANCE The rise of methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) represents a significant threat to global health, largely due to its resistance to many antibiotics and its ability to form durable biofilms. This study presents a novel approach to combating MRSA through the development of a series of quaternary phosphonium-based antibacterial compounds. Among these, the compound with the longest alkyl chain ([PTPP]·I) stands out for its remarkable effectiveness, inhibiting MRSA growth at low concentrations, disrupting biofilms by 96.6%, and demonstrating minimal cytotoxicity to human cells. The research highlights the crucial relationship between alkyl chain length and antibacterial activity, providing a new strategy for designing safer and more potent antimicrobial agents. These compounds target bacterial membranes and overcome resistance mechanisms, offering a promising solution for treating MRSA infections and addressing the broader issue of antibiotic resistance, potentially saving lives and alleviating the global healthcare burden.