Investigating Penetration and Antimicrobial Activity of Vector-Bicycle Conjugates

• DOI: 10.1021/acsinfecdis.3c00427
• Publication Date: 2024-06-12T15:54:37Z
• Authors: Andreas Hadjichar...; Hector Newman; Nick Lewis; Catherine Rowland; Nikolaos Bournakas; Steven J. Stanway; Michael Dawson; Michael J. Skynner; Paul Beswick
• Keywords: Penetration (warfare); Conjugate; Gram-Negative Bacteria

Growing antibiotic resistance is rapidly threatening the efficacy of treatments for Gram-negative infections. Bicycle molecules, constrained bicyclic peptides from diverse libraries generated by bacteriophage display that bind with high affinity to a chosen target are potential new class antibiotics. The generally impermeable bacterial outer membrane currently limits access bacteria. conjugation active offers an avenue penetration. Here, we investigate which physicochemical properties specific peptide (MAP), derived ixosin-B, could be tweaked enhance penetration conjugates generating multiple MAP-Bicycle conjugate variants. We demonstrate charge and hydrophobicity important factors, and, therefore, antimicrobial potency. Interestingly, show induction secondary structure, but not change in amphipathicity, vital effective membrane. These results offer insights into ways vectors designed deliver molecules (and other cargos) through biological membranes.