Abstract
Creative strategies for identifying new antibiotics are essential to addressing the looming threat of a post-antibiotic era. We here report the use of a targeted peptide phage display screen as a means of generating novel antimicrobial lipopeptides. Specifically, a library of phage displayed bicyclic peptides was screened against a biomolecular target based on the bacterial cell wall precursor lipid II. In doing so we identified unique lipid II binding peptides that upon lipidation were found to be active against a range of Gram-positive bacteria including clinically relevant strains of vancomycin resistant bacteria. Optimization of the peptide sequence led to variants with enhanced antibacterial activity and reduced hemolytic activity. Biochemical experiments further confirm a lipid II mediated mode of action for these new-to-nature antibacterial lipopeptides.
Highlights
The rapidly increasing incidence of drug resistant bacteria underscores the importance of employing new strategies for the discovery of novel antimicrobial compounds
In doing so we identified unique lipid II binding peptides that upon lipidation were found to be active against a range of Grampositive bacteria including clinically relevant strains of vancomycin resistant bacteria
It was considered that L-peptides selected in the screen that possess high affinity for natural lipid I/II might be toxic towards the E. coli used in the ampli cation step of the phage display experiment
Summary
For the peptide phage display screens here described we opted for a targeted approach aimed at identifying peptides capable of binding to the bacterial cell wall precursor lipid II (Fig. 1). Lipid II is an established target for numerous antibiotics.[15,16] Biosynthesized on the inner surface of the bacterial membrane, lipid II must be translocated to the extracellular surface before it can be incorporated into the cell wall. Edge Article symmetry arguments would be expected bind with equal affinity to native lipid I/II. Such so-called “mirror-image” strategies have previously been employed in identifying D-peptide ligands for various targets including HIV-1 gp41.20,21
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