Next-generation membrane-active glycopeptide antibiotics that also inhibit bacterial cell division.

Resistance to vancomycin, a life-saving drug against Gram-positive bacterial infections necessitates developing alternative therapeutics. Herein, we report vancomycin derivatives that assimilate mechanisms beyond d-Ala-d-Ala binding. The role of hydrophobicity towards the structure and function of the membrane-active vancomycin showed that alkyl-cationic substitutions favored broad-spectrum activity. The lead molecule, VanQAmC delocalized the cell division protein MinD in , implying an impact on bacterial cell division. Further examination of wild-type, GFP-FtsZ, or GFP-FtsI producing- and Δ mutants of revealed filamentous phenotypes and delocalization of the FtsI protein. The findings indicate that VanQAmC also inhibits bacterial cell division, a property previously unknown for glycopeptide antibiotics. The conjunction of multiple mechanisms contributes to its superior efficacy against metabolically active and inactive bacteria, wherein vancomycin is ineffective. Additionally, VanQAmC exhibits high efficacy against methicillin-resistant (MRSA) and in mouse models of infection.