Hart, Peter 'TWood, Thomas M.Tehrani, Kamaleddin Haj Mohammad EbrahimVan Harten, Roel M.Sleszynska, MalgorzataRebollo, Inmaculada RenteroHendrickx, Antoni P. A.Willems, Rob J. L.Breukink, EefjanMartin, Nathaniel I.2017-12-042017-12-042017-12-04201710.1039/c7sc03413jhttps://infoscience.epfl.ch/handle/20.500.14299/142509WOS:000415877000013Creative 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.text::journal::journal article::research article