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Copper Influences the Antibacterial Outcomes of a β-Lactamase-Activated Prochelator against Drug-Resistant Bacteria.

Publication ,  Journal Article
Zaengle-Barone, JM; Jackson, AC; Besse, DM; Becken, B; Arshad, M; Seed, PC; Franz, KJ
Published in: ACS Infect Dis
June 8, 2018

The unabated rise in bacterial resistance to conventional antibiotics, coupled with collateral damage to normal flora incurred by overuse of broad-spectrum antibiotics, necessitates the development of new antimicrobials targeted against pathogenic organisms. Here, we explore the antibacterial outcomes and mode of action of a prochelator that exploits the production of β-lactamase enzymes by drug-resistant bacteria to convert a nontoxic compound into a metal-binding antimicrobial agent directly within the microenvironment of pathogenic organisms. Compound PcephPT (phenylacetamido-cephem-pyrithione) contains a cephalosporin core linked to 2-mercaptopyridine N-oxide (pyrithione) via one of its metal-chelating atoms, which minimizes its preactivation interaction with metal ions and its cytotoxicity. Spectroscopic and chromatographic assays indicate that PcephPT releases pyrithione in the presence of β-lactamase-producing bacteria. The prochelator shows enhanced antibacterial activity against strains expressing β-lactamases, with bactericidal efficacy improved by the presence of low-micromolar copper in the growth medium. Metal analysis shows that cell-associated copper accumulation by the prochelator is significantly lower than that induced by pyrithione itself, suggesting that the location of pyrithione release influences biological outcomes. Low-micromolar (4-8 μg/mL) minimum inhibitory concentration (MIC) values of PcephPT in ceftriaxone-resistant bacteria compared with median lethal dose (LD50) values greater than 250 μM in mammalian cells suggests favorable selectivity. Further investigation into the mechanisms of prochelators will provide insight for the design of new antibacterial agents that manipulate cellular metallobiology as a strategy against infection.

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Published In

ACS Infect Dis

DOI

EISSN

2373-8227

Publication Date

June 8, 2018

Volume

4

Issue

6

Start / End Page

1019 / 1029

Location

United States

Related Subject Headings

  • beta-Lactamases
  • Molecular Structure
  • Microbial Sensitivity Tests
  • Humans
  • Gene Knockout Techniques
  • Escherichia coli
  • Drug Stability
  • Drug Resistance, Bacterial
  • Drug Design
  • Copper
 

Citation

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ICMJE
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Zaengle-Barone, J. M., Jackson, A. C., Besse, D. M., Becken, B., Arshad, M., Seed, P. C., & Franz, K. J. (2018). Copper Influences the Antibacterial Outcomes of a β-Lactamase-Activated Prochelator against Drug-Resistant Bacteria. ACS Infect Dis, 4(6), 1019–1029. https://doi.org/10.1021/acsinfecdis.8b00037
Zaengle-Barone, Jacqueline M., Abigail C. Jackson, David M. Besse, Bradford Becken, Mehreen Arshad, Patrick C. Seed, and Katherine J. Franz. “Copper Influences the Antibacterial Outcomes of a β-Lactamase-Activated Prochelator against Drug-Resistant Bacteria.ACS Infect Dis 4, no. 6 (June 8, 2018): 1019–29. https://doi.org/10.1021/acsinfecdis.8b00037.
Zaengle-Barone JM, Jackson AC, Besse DM, Becken B, Arshad M, Seed PC, et al. Copper Influences the Antibacterial Outcomes of a β-Lactamase-Activated Prochelator against Drug-Resistant Bacteria. ACS Infect Dis. 2018 Jun 8;4(6):1019–29.
Zaengle-Barone, Jacqueline M., et al. “Copper Influences the Antibacterial Outcomes of a β-Lactamase-Activated Prochelator against Drug-Resistant Bacteria.ACS Infect Dis, vol. 4, no. 6, June 2018, pp. 1019–29. Pubmed, doi:10.1021/acsinfecdis.8b00037.
Zaengle-Barone JM, Jackson AC, Besse DM, Becken B, Arshad M, Seed PC, Franz KJ. Copper Influences the Antibacterial Outcomes of a β-Lactamase-Activated Prochelator against Drug-Resistant Bacteria. ACS Infect Dis. 2018 Jun 8;4(6):1019–1029.
Journal cover image

Published In

ACS Infect Dis

DOI

EISSN

2373-8227

Publication Date

June 8, 2018

Volume

4

Issue

6

Start / End Page

1019 / 1029

Location

United States

Related Subject Headings

  • beta-Lactamases
  • Molecular Structure
  • Microbial Sensitivity Tests
  • Humans
  • Gene Knockout Techniques
  • Escherichia coli
  • Drug Stability
  • Drug Resistance, Bacterial
  • Drug Design
  • Copper