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

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