| Autor: |
Hadjicharalambous A; Department of Biochemistry, University of Cambridge, Cambridge CB2 1QN, U.K.; BicycleTx Limited, Portway Building, Granta Park, Cambridge CB21 6GS, U.K., Newman H; BicycleTx Limited, Portway Building, Granta Park, Cambridge CB21 6GS, U.K.; School of Life Sciences, University of Warwick, Coventry CV4 7AL, U.K., Lewis N; BicycleTx Limited, Portway Building, Granta Park, Cambridge CB21 6GS, U.K., Rowland C; BicycleTx Limited, Portway Building, Granta Park, Cambridge CB21 6GS, U.K., Bournakas N; BicycleTx Limited, Portway Building, Granta Park, Cambridge CB21 6GS, U.K., Stanway SJ; BicycleTx Limited, Portway Building, Granta Park, Cambridge CB21 6GS, U.K., Dawson M; BicycleTx Limited, Portway Building, Granta Park, Cambridge CB21 6GS, U.K., Skynner MJ; BicycleTx Limited, Portway Building, Granta Park, Cambridge CB21 6GS, U.K., Beswick P; BicycleTx Limited, Portway Building, Granta Park, Cambridge CB21 6GS, U.K. |
| Abstrakt: |
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 a potential new class of antibiotics. The generally impermeable bacterial outer membrane currently limits the access of peptides to bacteria. The conjugation of membrane active peptides offers an avenue for outer membrane penetration. Here, we investigate which physicochemical properties of a specific membrane active peptide (MAP), derived from ixosin-B, could be tweaked to enhance the penetration of conjugates by generating multiple MAP-Bicycle conjugate variants. We demonstrate that charge and hydrophobicity are important factors, which enhance penetration and, therefore, antimicrobial potency. Interestingly, we show that induction of secondary structure, but not a change in amphipathicity, is vital for effective penetration of the Gram-negative outer membrane. These results offer insights into the ways vectors could be designed to deliver Bicycle molecules (and other cargos) through biological membranes. |
