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A Cephalosporin Prochelator Inhibits New Delhi Metallo-β-lactamase 1 without Removing Zinc.

Publication ,  Journal Article
Jackson, AC; Zaengle-Barone, JM; Puccio, EA; Franz, KJ
Published in: ACS infectious diseases
May 2020

Antibacterial drug resistance is a rapidly growing clinical threat, partially due to expression of β-lactamase enzymes, which confer resistance to bacteria by hydrolyzing and inactivating β-lactam antibiotics. The increasing prevalence of metallo-β-lactamases poses a unique challenge, as currently available β-lactamase inhibitors target the active site of serine β-lactamases but are ineffective against the zinc-containing active sites of metallo-β-lactamases. There is an urgent need for metallo-β-lactamase inhibitors and antibiotics that circumvent resistance mediated by metallo-β-lactamases in order to extend the utility of existing β-lactam antibiotics for treating infection. Here we investigated the antibacterial chelator-releasing prodrug PcephPT (2-((((6R,7R)-2-carboxy-8-oxo-7-(2-phenylacetamido)-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl)methyl)thio) pyridine 1-oxide) as an inhibitor of New Delhi metallo-β-lactamase 1 (NDM-1). PcephPT is an experimental compound that we have previously shown inhibits growth of β-lactamase-expressing E. coli using a mechanism that is dependent on both copper availability and β-lactamase expression. Here, we found that PcephPT, in addition to being a copper-dependent antibacterial compound, inhibits hydrolysis activity of purified NDM-1with an IC50 of 7.6 μM without removing zinc from the active site and restores activity of the carbapenem antibiotic meropenem against NDM-1-producing E. coli. This work demonstrates that targeting a metal-binding pharmacophore to β-lactamase-producing bacteria is a promising strategy for inhibition of both bacterial growth and metallo-β-lactamases.

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Published In

ACS infectious diseases

DOI

EISSN

2373-8227

ISSN

2373-8227

Publication Date

May 2020

Volume

6

Issue

5

Start / End Page

1264 / 1272

Related Subject Headings

  • beta-Lactamases
  • beta-Lactamase Inhibitors
  • Zinc
  • Meropenem
  • Escherichia coli
  • Cephalosporins
  • 3207 Medical microbiology
  • 1108 Medical Microbiology
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Jackson, A. C., Zaengle-Barone, J. M., Puccio, E. A., & Franz, K. J. (2020). A Cephalosporin Prochelator Inhibits New Delhi Metallo-β-lactamase 1 without Removing Zinc. ACS Infectious Diseases, 6(5), 1264–1272. https://doi.org/10.1021/acsinfecdis.0c00083
Jackson, Abigail C., Jacqueline M. Zaengle-Barone, Elena A. Puccio, and Katherine J. Franz. “A Cephalosporin Prochelator Inhibits New Delhi Metallo-β-lactamase 1 without Removing Zinc.ACS Infectious Diseases 6, no. 5 (May 2020): 1264–72. https://doi.org/10.1021/acsinfecdis.0c00083.
Jackson AC, Zaengle-Barone JM, Puccio EA, Franz KJ. A Cephalosporin Prochelator Inhibits New Delhi Metallo-β-lactamase 1 without Removing Zinc. ACS infectious diseases. 2020 May;6(5):1264–72.
Jackson, Abigail C., et al. “A Cephalosporin Prochelator Inhibits New Delhi Metallo-β-lactamase 1 without Removing Zinc.ACS Infectious Diseases, vol. 6, no. 5, May 2020, pp. 1264–72. Epmc, doi:10.1021/acsinfecdis.0c00083.
Jackson AC, Zaengle-Barone JM, Puccio EA, Franz KJ. A Cephalosporin Prochelator Inhibits New Delhi Metallo-β-lactamase 1 without Removing Zinc. ACS infectious diseases. 2020 May;6(5):1264–1272.
Journal cover image

Published In

ACS infectious diseases

DOI

EISSN

2373-8227

ISSN

2373-8227

Publication Date

May 2020

Volume

6

Issue

5

Start / End Page

1264 / 1272

Related Subject Headings

  • beta-Lactamases
  • beta-Lactamase Inhibitors
  • Zinc
  • Meropenem
  • Escherichia coli
  • Cephalosporins
  • 3207 Medical microbiology
  • 1108 Medical Microbiology