Exploitation of antibiotic resistance as a novel drug target: development of a β-lactamase-activated antibacterial prodrug.
File(s)
Published version
Author(s)
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.
Date Issued
2019-05-09
Date Acceptance
2019-04-22
Citation
Journal of Medicinal Chemistry, 2019, 62 (9), pp.4411-4425
ISSN
0022-2623
Publisher
American Chemical Society (ACS)
Start Page
4411
End Page
4425
Journal / Book Title
Journal of Medicinal Chemistry
Volume
62
Issue
9
Copyright Statement
© 2019 American Chemical Society. This is an open access article published under a Creative Commons Attribution (CC-BY) License ( https://pubs.acs.org/page/policy/authorchoice_ccby_termsofuse.html ), which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
Sponsor
IP2IPO Innovations Limited
Wellcome Trust
Wellcome Trust
Grant Number
6846
204337/Z/16/Z
107660/Z/15/Z
Subjects
Science & Technology
Life Sciences & Biomedicine
Chemistry, Medicinal
Pharmacology & Pharmacy
ESCHERICHIA-COLI
KLEBSIELLA-PNEUMONIAE
QUINOLONE ACTION
DUAL-MODE
CEPHALOSPORIN
EPIDEMIOLOGY
MECHANISMS
ESTERS
HYDROLYSIS
MICROBIOTA
Medicinal & Biomolecular Chemistry
0304 Medicinal and Biomolecular Chemistry
1115 Pharmacology and Pharmaceutical Sciences
0305 Organic Chemistry
Publication Status
Published
Date Publish Online
2019-04-22