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


ABSTRACT: Expression of ?-lactamase is the single most prevalent determinant of antibiotic resistance, rendering bacteria resistant to ?-lactam antibiotics. In this article, we describe the development of an antibiotic prodrug that combines ciprofloxacin with a ?-lactamase-cleavable motif. The prodrug is only bactericidal after activation by ?-lactamase. Bactericidal activity comparable to ciprofloxacin is demonstrated against clinically relevant E. coli isolates expressing diverse ?-lactamases; bactericidal activity was not observed in strains without ?-lactamase. These findings demonstrate that it is possible to exploit antibiotic resistance to selectively target ?-lactamase-producing bacteria using our prodrug approach, without adversely affecting bacteria that do not produce ?-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.

SUBMITTER: Evans LE 

PROVIDER: S-EPMC6511942 | BioStudies | 2019-01-01

REPOSITORIES: biostudies

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