Skip to content

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

Research output: Contribution to journalArticle

Original languageEnglish
Pages (from-to)4411-4425
Number of pages15
JournalJournal of Medicinal Chemistry
Volume62
Issue number9
Early online date22 Apr 2019
DOIs
DateAccepted/In press - 22 Apr 2019
DateE-pub ahead of print - 22 Apr 2019
DatePublished (current) - 9 May 2019

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 prodrug that combines ciprofloxacin with a β-lactamase-cleavable motif. The prodrug 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 prodrug 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.

Download statistics

No data available

Documents

Documents

  • Full-text PDF (final published version)

    Rights statement: This is the final published version of the article (version of record). It first appeared online via ACS at https://pubs.acs.org/doi/10.1021/acs.jmedchem.8b01923 . Please refer to any applicable terms of use of the publisher.

    Final published version, 3 MB, PDF-document

    Licence: CC BY

DOI

View research connections

Related faculties, schools or groups