Two-Tailed Dynamic Covalent Amphiphile Combats Bacterial Biofilms

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 the two-tailed antimicrobial amphiphiles (T(2)A(2)) composed of nitric oxide (NO)-donor (diethylenetriamine NONOate, DN) and various natural aldehydes are reported. 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, the 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.

Automated summary

This research reports a novel class of antimicrobial molecules (T(2)A(2)) composed of nitric oxide (NO)-donor (DN) and various natural aldehydes, which self-assemble into nanoparticles and exhibit significant bactericidal efficacy. Cin-T(2)A(2) can kill multidrug-resistant staphylococci and eradicate their biofilms through multiple mechanisms. Furthermore, Cin-T(2)A(2) rapidly eradicates bacteria and alleviates inflammation in murine infection models.