Alkyl-Aryl-Vancomycins: Multimodal Glycopeptides with Weak Dependence on the Bacterial Metabolic State

Abstract

Resistance to last-resort antibiotics such as vancomycin for Gram-positive bacterial infections necessitates the development of new therapeutics. Furthermore, the ability of bacteria to survive antibiotic therapy through formation of biofilms and persister cells complicates treatment. Toward this, we report alkyl-aryl-vancomycins (AAVs), with high potency against vancomycin-resistant enterococci and staphylococci. Unlike vancomycin, the lead compound AAV-qC10 was bactericidal and weakly dependent on bacterial metabolism. This resulted in complete eradication of non-growing cells of MRSA and disruption of its biofilms. In addition to inhibiting cell wall biosynthesis like vancomycin, AAV-qC10 also depolarizes and permeabilizes the membrane. More importantly, the compound delocalized the cell division protein MinD, thereby impairing bacterial growth through multiple pathways. The potential of AAV-qC10 is exemplified by its superior efficacy against MRSA in a murine thigh infection model as compared to vancomycin. This work paves the way for structural optimization and drug development for combating drug-resistant bacterial infections.