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A Multidisciplinary Approach toward Identification of Antibiotic Scaffolds for Acinetobacter baumannii

Lookup NU author(s): Dr Satya Bhamidimarri, Dr Michael Zahn, Professor Bert van den Berg

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Abstract

© 2018 Elsevier Ltd Research efforts to discover potential new antibiotics for Gram-negative bacteria suffer from high attrition rates due to the synergistic action of efflux systems and the limited permeability of the outer membrane (OM). One strategy to overcome the OM permeability barrier is to identify small molecules that are natural substrates for abundant OM channels and use such compounds as scaffolds for the design of efficiently permeating antibacterials. Here we present a multidisciplinary approach to identify such potential small-molecule scaffolds. Focusing on the pathogenic bacterium Acinetobacter baumannii, we use OM proteomics to identify DcaP as the most abundant channel during infection in rodents. The X-ray crystal structure of DcaP reveals a trimeric, porin-like structure and suggests that dicarboxylic acids are potential transport substrates. Electrophysiological experiments and all-atom molecular dynamics simulations confirm this notion and provide atomistic information on likely permeation pathways and energy barriers for several small molecules, including a clinically relevant β-lactamase inhibitor. © 2018 Elsevier Ltd Bhamidimarri et al. present a multidisciplinary approach to identify potential antibiotic scaffolds in Acinetobacter baumannii. OM proteomics identify DcaP as the most abundant channel. X-ray crystallography reveals a trimeric porin-like structure and suggests dicarboxylic acids as potential substrates. Electrophysiology and MD simulations provide detailed information on small-molecule permeation pathways.

Publication metadata

Author(s): Bhamidimarri SP, Zahn M, Prajapati JD, Schleberger C, Soderholm S, Hoover J, West J, Kleinekathofer U, Bumann D, Winterhalter M, van den Berg B

Publication type: Article

Publication status: Published

Journal: Structure

Year: 2019

Volume: 27

Issue: 2

Pages: 268-280.e6

Print publication date: 05/02/2019

Online publication date: 13/12/2018

Acceptance date: 23/10/2018

ISSN (print): 0969-2126

ISSN (electronic): 1878-4186

Publisher: Cell Press

URL: https://doi.org/10.1016/j.str.2018.10.021

DOI: 10.1016/j.str.2018.10.021

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