@article{Evans:2019:10.1021/acs.jmedchem.8b01923,
author = {Evans, LE and Krishna, A and Ma, Y and Webb, TE and Marshall, DC and Tooke, CL and Spencer, J and Clarke, TB and Armstrong, A and Edwards, A},
doi = {10.1021/acs.jmedchem.8b01923},
journal = {Journal of Medicinal Chemistry},
pages = {4411--4425},
title = {Exploitation of antibiotic resistance as a novel drug target: development of a β-lactamase-activated antibacterial prodrug.},
url = {http://dx.doi.org/10.1021/acs.jmedchem.8b01923},
volume = {62},
year = {2019}
}

Download

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  - 

Download