α-Bromocinnamaldehyde combats ESKAPE pathogens through dual bactericidal mechanism.

Trans-cinnamaldehyde (CA), a natural compound from cinnamon oil, is known for its broad-spectrum but limited antibacterial activity. In this study, we synthesized and evaluated a series of CA derivatives, identifying α-Bromocinnamaldehyde (BCA) as the most potent antibacterial agent against ESKAPE pathogens. Through minimum inhibitory concentration (MIC) assays and a detailed structure-activity analysis, we determined that BCA’s enhanced antibacterial potency is due to the α-bromine substitution, the aldehyde group, and the conjugated double bond. In an in vivo septic mouse model infected with NDM-1-producing E. coli, BCA treatment significantly improved survival rates, and no acute renal or liver toxicity was observed at therapeutic doses. Mechanistic studies, including scanning electron microscopy, fluorescence microscopy, Gram staining, light-scattering assays for FtsZ polymerization, and GTP hydrolysis assays, have elucidated that BCA exerts its bactericidal effects through a dual-mechanism approach. Firstly, BCA increases membrane permeability, disrupting the integrity of the bacterial cell membrane. Secondly, it inhibits bacterial cell division, likely by interfering with the polymerization of FtsZ, a key protein involved in cell division, and affecting GTP hydrolysis processes essential for cell division progression. These findings highlight BCA’s dual bactericidal mechanisms and support its potential as a promising therapeutic agent for treating multidrug-resistant bacterial infections.