The rapid emergence of antibiotic resistance urgently calls for novel and more effective ways to treat bacterial infections. Vancomycin, a powerful antibiotic that has been used in clinic for decades, kills bacteria by sequestering lipid II, thus inhibiting peptidoglycan biosynthesis. The unique mechanism of lipid sequestration is made possible with the highly crosslinked structure of vancomycin. Specifically, we have developed synthetic methods to access peptides that display novel multicyclic structures and incorporate reversible covalent warheads. These synthetic peptides are structurally complex and hold great potential to serve as vancomycin mimics. Importantly, our synthetic strategies enable facile constrcution of peptide libraries, which gives a general platform for discovering synthetic receptors for lipids of interest. Specifically, we have identified covalent binders of Lys-PG, a bacterial lipid believed to afford resistance to host defense peptides. Characterzation of the peptide hits reveals that covalent binding and modification of Lys-PG makes bacterial cells more prone to cell killing by cationic antibitics. This result indicates that targeting Lys-PG can be a viable strategy to facilitate bacterial clearance by host defense mechanisms.

Toward vancomycin-like antibiotics: Targeting bacterial lipids with synthetic peptides

254th National Meeting (2017)

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