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

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

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