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Exploiting innate immune cell activation of a copper-dependent antimicrobial agent during infection.

Publication ,  Journal Article
Festa, RA; Helsel, ME; Franz, KJ; Thiele, DJ
Published in: Chemistry & biology
August 2014

Recalcitrant microbial infections demand new therapeutic options. Here we present an approach that exploits two prongs of the host immune cell antimicrobial response: the oxidative burst and the compartmentalization of copper (Cu) within phagolysosomes. The prochelator QBP is a nontoxic protected form of 8-hydroxyquinoline (8HQ) in which a pinanediol boronic ester blocks metal ion coordination by 8HQ. QBP is deprotected via reactive oxygen species produced by activated macrophages, creating 8HQ and eliciting Cu-dependent killing of the fungal pathogen Cryptococcus neoformans in vitro and in mouse pulmonary infection. 8HQ ionophoric activity increases intracellular Cu, overwhelming the Cu-resistance mechanisms of C. neoformans to elicit fungal killing. The Cu-dependent antimicrobial activity of 8HQ against a spectrum of microbial pathogens suggests that this strategy may have broad utility. The conditional activation of Cu ionophores by innate immune cells intensifies the hostile antimicrobial environment and represents a promising approach to combat infectious disease.

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Published In

Chemistry & biology

DOI

EISSN

1879-1301

ISSN

1074-5521

Publication Date

August 2014

Volume

21

Issue

8

Start / End Page

977 / 987

Related Subject Headings

  • Structure-Activity Relationship
  • Organometallic Compounds
  • Organic Chemistry
  • Molecular Structure
  • Microbial Sensitivity Tests
  • Mice
  • Macrophages
  • Immunity, Innate
  • Female
  • Dose-Response Relationship, Drug
 

Citation

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Festa, R. A., Helsel, M. E., Franz, K. J., & Thiele, D. J. (2014). Exploiting innate immune cell activation of a copper-dependent antimicrobial agent during infection. Chemistry & Biology, 21(8), 977–987. https://doi.org/10.1016/j.chembiol.2014.06.009
Festa, Richard A., Marian E. Helsel, Katherine J. Franz, and Dennis J. Thiele. “Exploiting innate immune cell activation of a copper-dependent antimicrobial agent during infection.Chemistry & Biology 21, no. 8 (August 2014): 977–87. https://doi.org/10.1016/j.chembiol.2014.06.009.
Festa RA, Helsel ME, Franz KJ, Thiele DJ. Exploiting innate immune cell activation of a copper-dependent antimicrobial agent during infection. Chemistry & biology. 2014 Aug;21(8):977–87.
Festa, Richard A., et al. “Exploiting innate immune cell activation of a copper-dependent antimicrobial agent during infection.Chemistry & Biology, vol. 21, no. 8, Aug. 2014, pp. 977–87. Epmc, doi:10.1016/j.chembiol.2014.06.009.
Festa RA, Helsel ME, Franz KJ, Thiele DJ. Exploiting innate immune cell activation of a copper-dependent antimicrobial agent during infection. Chemistry & biology. 2014 Aug;21(8):977–987.

Published In

Chemistry & biology

DOI

EISSN

1879-1301

ISSN

1074-5521

Publication Date

August 2014

Volume

21

Issue

8

Start / End Page

977 / 987

Related Subject Headings

  • Structure-Activity Relationship
  • Organometallic Compounds
  • Organic Chemistry
  • Molecular Structure
  • Microbial Sensitivity Tests
  • Mice
  • Macrophages
  • Immunity, Innate
  • Female
  • Dose-Response Relationship, Drug