Influence of Lipophilicity on the Antibacterial Activity of Polymyxin Derivatives and on Their Ability to Act As Potentiators of Rifampicin

Overview

Journal ACS Infect Dis

Specialties Infectious Diseases
Microbiology
Pharmacology

Date 2021 Mar 10

PMID 33688718

Citations 7

Authors

Pamela Brown

Omar Abdulle

Steven Boakes

Naomi Divall

Esther Duperchy

Sonia Ganeshwaran

Roy Lester

Stephen Moss

Dean Rivers

Mona Simonovic

Jaspal Singh

Steven Stanway

Antoinette Wilson

Michael J Dawson

Affiliations

Soon will be listed here.

Abstract

Novel polymyxin derivatives are often classified either as having direct activity against Gram-negative pathogens or as compounds inactive in their own right, which through permeabilization of the outer membrane act as potentiators of other antibiotics. Here, we report the systematic investigation of the influence of lipophilicity on microbiological activity (including against strains with reduced susceptibility to polymyxins), potentiation of rifampicin, and toxicity within a series of next-generation polymyxin nonapeptides. We demonstrate that the lipophilicity at the N-terminus and amino acids 6 and 7 in the cyclic peptide core is interchangeable and that the activity, ability to potentiate, and cytotoxicity all appear to be primarily driven by overall lipophilicity. Our work also suggests that the characterization of a polymyxin molecule as either a direct acting compound or a potentiator is more of a continuum that is strongly influenced by lipophilicity rather than as a result of fundamentally different modes-of-action.

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