Tetrabromobisphenol A (TBBPA) inhibits Bacillus subtilis as a Membrane Active Antibacterial Agent

ABSTRACT Antimicrobial resistance (AMR) is a pressing global public health crisis, necessitating novel antimicrobial agents and mechanistic insights. Tetrabromobisphenol A (TBBPA), a widely used brominated flame retardant, exhibits potent activity against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus (MRSA) without inducing resistance, yet its mode of action remains unclear. Using Bacillus subtilis as a model, we investigated TBBPA’s antibacterial mechanism via extensive bacterial cytological profiling, fluorescence imaging, and mutant validation. We found that TBBPA causes membrane depolarization and disruption, based on Thioflavin T release, MinD mislocalization, FM5-95 fluorescence aggregation, and propidium iodide penetration. In fact, TBBPA can destabilizes giant unilamellar lipid vesicles in vitro . The induced membrane damage triggers several downstream effects, including MreB immobilization, which impairs cell wall synthesis, inhibition of DNA replication and translation, and increased autolysin activation leading to cell lysis. In conclusion, this study suggests that TBBPA directly targets the cell membrane, causing disruption of multiple essential processes, and leads to activation of autolysins, resulting in lysis. These findings highlight TBBPA’s prospective utility as an anti-Gram-positive agent; nevertheless, concerns over its potential side effects necessitate further investigations into its safety profile prior to clinical translation.