Exploitation of Antibiotic Resistance as a Novel Drug Target: Development of a β-Lactamase-Activated Antibacterial Prodrug

Lindsay E Evans, Aishwarya Krishna, Yajing Ma, Thomas E Webb, Dominic C Marshall, Catherine L Tooke, James Spencer, Thomas B Clarke, Alan Armstrong, Andrew M Edwards

Research output: Contribution to journalArticle (Academic Journal)

3 Citations (Scopus)
235 Downloads (Pure)

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.
Original languageEnglish
Pages (from-to)4411-4425
Number of pages15
JournalJournal of Medicinal Chemistry
Volume62
Issue number9
Early online date22 Apr 2019
DOIs
Publication statusPublished - 9 May 2019

Fingerprint Dive into the research topics of 'Exploitation of Antibiotic Resistance as a Novel Drug Target: Development of a β-Lactamase-Activated Antibacterial Prodrug'. Together they form a unique fingerprint.

  • Cite this