Exploitation of antibiotic resistance as a novel drug target: development of a β-lactamase-activated antibacterial prodrug

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Title: Exploitation of antibiotic resistance as a novel drug target: development of a β-lactamase-activated antibacterial prodrug
Authors: Evans, LE
Krishna, A
Ma, Y
Webb, TE
Marshall, DC
Tooke, CL
Spencer, J
Clarke, TB
Armstrong, A
Edwards, A
Item Type: Journal Article
Abstract: Expression of β-lactamase is the single most prevalent determinant of antibiotic resistance, rendering bacteria resistant to β-lactam antibiotics. In this article, we describe the development of an antibiotic pro-drug that combines ciprofloxacin with a β-lactamase-cleavable motif. The pro-drug is only bactericidal after activation by β-lactamase. Bactericidal activity comparable to ciprofloxacin is demonstrated against clinically-relevant E. coli isolates expressing diverse β-lactamases; bactericidal activity was not observed in strains without β-lactamase. These findings demonstrate that it is possible to exploit antibiotic resistance to selectively target β-lactamase-producing bacteria using our pro-drug approach, without adversely affecting bacteria that do not produce β-lactamase. This paves the way for selective targeting of drug-resistant pathogens without disrupting or selecting for resistance within the microbiota, reducing the rate of secondary infections and subsequent antibiotic use.
Issue Date: 22-Apr-2019
Date of Acceptance: 22-Apr-2019
URI: http://hdl.handle.net/10044/1/69176
DOI: https://doi.org/10.1021/acs.jmedchem.8b01923
ISSN: 0022-2623
Publisher: American Chemical Society (ACS)
Journal / Book Title: Journal of Medicinal Chemistry
Copyright Statement: © 2019 American Chemical Society. This document is the Accepted Manuscript version of a Published Work that appeared in final form in [Journal of Medicinal Chemistry], after peer review and technical editing by the publisher. To access the final edited and published work see [https://doi.org/10.1021/acs.jmedchem.8b01923].
Sponsor/Funder: Imperial Innovations Ltd
Wellcome Trust
Funder's Grant Number: 6846
204337/Z/16/Z
Keywords: Medicinal & Biomolecular Chemistry
0304 Medicinal and Biomolecular Chemistry
1115 Pharmacology and Pharmaceutical Sciences
0305 Organic Chemistry
Publication Status: Published online
Embargo Date: 2020-04-22
Online Publication Date: 2019-04-22
Appears in Collections:Department of Medicine



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