TY - JOUR AB - 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. AU - Evans,LE AU - Krishna,A AU - Ma,Y AU - Webb,TE AU - Marshall,DC AU - Tooke,CL AU - Spencer,J AU - Clarke,TB AU - Armstrong,A AU - Edwards,A DO - 10.1021/acs.jmedchem.8b01923 EP - 4425 PY - 2019/// SN - 0022-2623 SP - 4411 TI - Exploitation of antibiotic resistance as a novel drug target: development of a β-lactamase-activated antibacterial prodrug. T2 - Journal of Medicinal Chemistry UR - http://dx.doi.org/10.1021/acs.jmedchem.8b01923 UR - http://hdl.handle.net/10044/1/69176 VL - 62 ER -