<p>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 <i>E. coli</i>, 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.</p> Graphical abstract <p> This study explores chemical modifications of cinnamaldehyde (CA) to enhance its antibacterial activity. α-Bromocinnamaldehyde (BCA), a key derivative, exhibits potent, broad-spectrum activity against multidrug-resistant ESKAPE pathogens. Mechanistic insights reveal that BCA disrupts bacterial membranes and inhibits cell division, highlighting its potential as a novel antibacterial agent in the fight against antibiotic-resistant infections</p> <p></p>