Novel Strategies towards the Inhibition of ATP-Binding Cassette (ABC) Transporters from Pathogenic Bacteria
type: CreativeWork
description: Multidrug transporters in the ATP-Binding Cassette (ABC) superfamily play critical roles in pathogenic bacteria. These transport systems are particularly important in conferring antibiotic resistance on the cell by mediating the efflux of a wide range of structurally unrelated compounds and the transport of lipids that form antibiotic impervious membrane structures. Identifying novel antibiotic targets and strategies is required to address the ever-growing antibiotic crisis. ABC transporters are an untapped pool of potential targets. Two examples are the essential lipid transporter MsbA, from *Escherichia coli* and other pathogenic Enterobacteria, and the multidrug efflux transporter PatAB, that is upregulated in fluoroquinolone resistant *Streptococcus pneumoniae*. These proteins primarily utilise nucleotide hydrolysis to drive transport against the inwardly-directed concentration gradient across the cell plasma membrane. Current strategies to inhibit these transporters utilise small molecule drugs that often resemble the transported substrates or that target hydrophobic pockets in the transmembrane domain. While some promising steps have been made, studies of inhibition of bacterial transporters still need to catch up to their eukaryotic counterparts. This work aimed to elucidate the characteristics of inhibition of MsbA and PatAB while introducing novel strategies to target the ABC superfamily, summarising the state of drug development against these proteins and the available functional techniques to study inhibition. First, extensive characterisation of the interactions of PatAB with its transport substrates revealed two distinct responses to substrate binding. While many of these substrates did not affect the rate of nucleotide hydrolysis, suggesting an uncoupling of their transport from nucleotide hydrolysis, a subclass of substrates including ethidium, propidium and aminocoumarin antibiotics showed potent non-competitive inhibition of hydrolysis. This was obs…
abstract: Multidrug transporters in the ATP-Binding Cassette (ABC) superfamily play critical roles in pathogenic bacteria. These transport systems are particularly important in conferring antibiotic resistance on the cell by mediating the efflux of a wide range of structurally unrelated compounds and the transport of lipids that form antibiotic impervious membrane structures. Identifying novel antibiotic targets and strategies is required to address the ever-growing antibiotic crisis. ABC transporters are an untapped pool of potential targets. Two examples are the essential lipid transporter MsbA, from *Escherichia coli* and other pathogenic Enterobacteria, and the multidrug efflux transporter PatAB, that is upregulated in fluoroquinolone resistant *Streptococcus pneumoniae*. These proteins primarily utilise nucleotide hydrolysis to drive transport against the inwardly-directed concentration gradient across the cell plasma membrane. Current strategies to inhibit these transporters utilise small molecule drugs that often resemble the transported substrates or that target hydrophobic pockets in the transmembrane domain. While some promising steps have been made, studies of inhibition of bacterial transporters still need to catch up to their eukaryotic counterparts. This work aimed to elucidate the characteristics of inhibition of MsbA and PatAB while introducing novel strategies to target the ABC superfamily, summarising the state of drug development against these proteins and the available functional techniques to study inhibition. First, extensive characterisation of the interactions of PatAB with its transport substrates revealed two distinct responses to substrate binding. While many of these substrates did not affect the rate of nucleotide hydrolysis, suggesting an uncoupling of their transport from nucleotide hydrolysis, a subclass of substrates including ethidium, propidium and aminocoumarin antibiotics showed potent non-competitive inhibition of hydrolysis. This was obs…
author: Guffick, Charlotte
language: eng
keywords: ABC Transporter, Antimicrobial Resistance, Drug Transport, Membrane Proteins
license: https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/2f176da5-ef98-4d9e-8ee8-37bfa8be115b/download
license: http://purl.org/NET/rdflicense/allrightsreserved
date published: 2022-12-30
date modified: 2026-07-22T22:24:24Z
provider: Cambridge University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Cambridge

PropertyValue
property ID: DOI
value: 10.17863/CAM.97214