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

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.