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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Jackson, AC; Zaengle-Barone, JM; Puccio, EA; Franz, KJ

Published Date

  • May 2020

Published In

Volume / Issue

  • 6 / 5

Start / End Page

  • 1264 - 1272

PubMed ID

  • 32298084

Pubmed Central ID

  • 32298084

Electronic International Standard Serial Number (EISSN)

  • 2373-8227

International Standard Serial Number (ISSN)

  • 2373-8227

Digital Object Identifier (DOI)

  • 10.1021/acsinfecdis.0c00083

Language

  • eng