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

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Exploitation of Antibiotic Resistance as a Novel Drug Target : Development of a β-Lactamase-Activated Antibacterial Prodrug. / Evans, Lindsay E; Krishna, Aishwarya; Ma, Yajing; Webb, Thomas E; Marshall, Dominic C; Tooke, Catherine L; Spencer, James; Clarke, Thomas B; Armstrong, Alan; Edwards, Andrew M.

In: Journal of Medicinal Chemistry, Vol. 62, No. 9, 09.05.2019, p. 4411-4425.

Research output: Contribution to journalArticle

Harvard

Evans, LE, Krishna, A, Ma, Y, Webb, TE, Marshall, DC, Tooke, CL, Spencer, J, Clarke, TB, Armstrong, A & Edwards, AM 2019, 'Exploitation of Antibiotic Resistance as a Novel Drug Target: Development of a β-Lactamase-Activated Antibacterial Prodrug', Journal of Medicinal Chemistry, vol. 62, no. 9, pp. 4411-4425. https://doi.org/10.1021/acs.jmedchem.8b01923

APA

Evans, L. E., Krishna, A., Ma, Y., Webb, T. E., Marshall, D. C., Tooke, C. L., ... Edwards, A. M. (2019). Exploitation of Antibiotic Resistance as a Novel Drug Target: Development of a β-Lactamase-Activated Antibacterial Prodrug. Journal of Medicinal Chemistry, 62(9), 4411-4425. https://doi.org/10.1021/acs.jmedchem.8b01923

Vancouver

Author

Evans, Lindsay E ; Krishna, Aishwarya ; Ma, Yajing ; Webb, Thomas E ; Marshall, Dominic C ; Tooke, Catherine L ; Spencer, James ; Clarke, Thomas B ; Armstrong, Alan ; Edwards, Andrew M. / Exploitation of Antibiotic Resistance as a Novel Drug Target : Development of a β-Lactamase-Activated Antibacterial Prodrug. In: Journal of Medicinal Chemistry. 2019 ; Vol. 62, No. 9. pp. 4411-4425.

Bibtex

@article{b939cb1bc5344d03b7f308f06ff93ab2,
title = "Exploitation of Antibiotic Resistance as a Novel Drug Target: Development of a β-Lactamase-Activated Antibacterial Prodrug",
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.",
author = "Evans, {Lindsay E} and Aishwarya Krishna and Yajing Ma and Webb, {Thomas E} and Marshall, {Dominic C} and Tooke, {Catherine L} and James Spencer and Clarke, {Thomas B} and Alan Armstrong and Edwards, {Andrew M}",
year = "2019",
month = "5",
day = "9",
doi = "10.1021/acs.jmedchem.8b01923",
language = "English",
volume = "62",
pages = "4411--4425",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "9",

}

RIS - suitable for import to EndNote

TY - JOUR

T1 - Exploitation of Antibiotic Resistance as a Novel Drug Target

T2 - Development of a β-Lactamase-Activated Antibacterial Prodrug

AU - Evans, Lindsay E

AU - Krishna, Aishwarya

AU - Ma, Yajing

AU - Webb, Thomas E

AU - Marshall, Dominic C

AU - Tooke, Catherine L

AU - Spencer, James

AU - Clarke, Thomas B

AU - Armstrong, Alan

AU - Edwards, Andrew M

PY - 2019/5/9

Y1 - 2019/5/9

N2 - 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.

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 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.

UR - http://www.scopus.com/inward/record.url?scp=85065536377&partnerID=8YFLogxK

U2 - 10.1021/acs.jmedchem.8b01923

DO - 10.1021/acs.jmedchem.8b01923

M3 - Article

VL - 62

SP - 4411

EP - 4425

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 9

ER -