Lipid Tales: Optimizing Arylomycin Membrane Anchors

Overview

Journal ACS Med Chem Lett

Publisher American Chemical Society

Specialty Chemistry

Date 2023 Nov 17

PMID 37974942

Authors

Michael F T Koehler

Yi-Chen Chen

Yongsheng Chen

Yuan Chen

James J Crawford

Matthew R Durk

Keira Garland

Emily J Hanan

Robert I Higuchi

Huiyong Hu

Cuong Q Ly

Prasuna G Paraselli

Tucker C Roberts

Jacob B Schwarz

Peter A Smith

Zhiyong Yu

Christopher E Heise

Affiliations

Soon will be listed here.

Abstract

Multidrug-resistant bacteria are spreading at alarming rates, and despite extensive efforts, no new antibiotic class with activity against Gram-negative bacteria has been approved in over 50 years. LepB inhibitors (LepBi) based on the arylomycin class of natural products are a novel class of antibiotics and function by inhibiting the bacterial type I signal peptidase (SPase) in Gram-negative bacteria. One critical aspect of LepBi development involves optimization of the membrane-anchored lipophilic portion of the molecule. We therefore developed an approach that assesses the effect of this portion on the complicated equilibria of plasma protein binding, crossing the outer membrane of Gram-negative bacteria and anchoring in the bacterial inner membrane to facilitate SPase binding. Our findings provide important insights into the development of antibacterial agents where the target is associated with the inner membrane of Gram-negative bacteria.

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