Drug combination provides an efficient pathway to combat drug resistance in bacteria and bacterial biofilms. However, the facile methodology to construct the drug combinations and their applications in nanocomposites is still lacking. Here we report the two-tailed antimicrobial amphiphiles (T 2 A 2 ) composed of nitric oxide (NO)-donor (diethylenetriamine NONOate, DN) and various natural aldehydes. T 2 A 2 self-assemble into nanoparticles due to their amphiphilic nature, with remarkably low critical aggregation concentration. The representative cinnamaldehyde (Cin)-derived T 2 A 2 (Cin-T 2 A 2 ) assemblies demonstrate excellent bactericidal efficacy, notably higher than free Cin and free DN. Cin-T 2 A 2 assemblies kill multidrug-resistant staphylococci and eradicate their biofilms via multiple mechanisms, as proved by mechanism studies, molecular dynamics simulations, proteomics, and metabolomics. Furthermore, Cin-T 2 A 2 assemblies rapidly eradicate bacteria and alleviate inflammation in the subsequent murine infection models. Together, our Cin-T 2 A 2 assemblies may provide an efficient, non-antibiotic alternative in combating the ever-increasing threat of drug-resistant bacteria and their biofilms. This article is protected by copyright. All rights reserved.
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