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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Festa, RA; Helsel, ME; Franz, KJ; Thiele, DJ

Published Date

  • August 2014

Published In

Volume / Issue

  • 21 / 8

Start / End Page

  • 977 - 987

PubMed ID

  • 25088681

Pubmed Central ID

  • 25088681

Electronic International Standard Serial Number (EISSN)

  • 1879-1301

International Standard Serial Number (ISSN)

  • 1074-5521

Digital Object Identifier (DOI)

  • 10.1016/j.chembiol.2014.06.009

Language

  • eng