title: Exploiting innate immune cell activation of a copper-dependent antimicrobial agent during infection.
abstract: 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.
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Festa
authors.affiliation: Department of Chemistry, Duke University, Durham, NC 27708, USA.
authors.forename: Marian E
authors.initials: ME
authors.lastname: Helsel
authors.affiliation: Department of Chemistry, Duke University, Durham, NC 27708, USA. Electronic address: katherine.franz@duke.edu.
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Franz
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA. Electronic address: dennis.thiele@duke.edu.
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Thiele
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D003300:Copper / Q000737:chemistry / Q000494:pharmacology*; D003453:Cryptococcosis / Q000188:drug therapy*; D003454:Cryptococcus / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D007113:Immunity, Innate; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D051379:Mice; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000935:Antifungal Agents; D009942:Organometallic Compounds; D003300:Copper
references.citation: Infect Immun. 2010 May;78(5):2312-9
references.pmid: 20231415
references.citation: Int J Toxicol. 2006;25 Suppl 1:1-9
references.pmid: 16835127
references.citation: FEBS Lett. 2000 Jun 16;475(2):121-6
references.pmid: 10858501
references.citation: Toxicol Appl Pharmacol. 1963 Sep;5:599-604
references.pmid: 14068277
references.citation: Am J Clin Nutr. 1995 Aug;62(2):412-6
references.pmid: 7625350
references.citation: J Biol Inorg Chem. 2010 Feb;15(2):259-69
references.pmid: 19809836
references.citation: Neuron. 2008 Jul 10;59(1):43-55
references.pmid: 18614028
references.citation: J Antimicrob Chemother. 2010 Jul;65(7):1424-7
references.pmid: 20435781
references.citation: J Bacteriol. 2007 Mar;189(5):1616-26
references.pmid: 17189367
references.citation: N Engl J Med. 2013 Apr 4;368(14):1291-1302
references.pmid: 23550668
references.citation: J Alzheimers Dis. 2010;21(4):1249-62
references.pmid: 21504115
references.citation: Biochem J. 1975 Jun;147(3):401-10
references.pmid: 810137
references.citation: Carcinogenesis. 1996 Mar;17(3):545-50
references.pmid: 8631142
references.citation: Mol Microbiol. 2011 Sep;81(6):1560-76
references.pmid: 21819456
references.citation: Biochem J. 2011 Jun 1;436(2):481-91
references.pmid: 21426304
references.citation: J Biol Chem. 2012 Feb 3;287(6):4107-20
references.pmid: 22147697
references.citation: Dalton Trans. 2012 Apr 21;41(15):4530-5
references.pmid: 22354329
references.citation: Chem Res Toxicol. 2011 May 16;24(5):687-97
references.pmid: 21434648
references.citation: Antimicrob Agents Chemother. 2007 Dec;51(12):4420-6
references.pmid: 17908943
references.citation: J Biol Chem. 2011 Apr 1;286(13):11047-55
references.pmid: 21258123
references.citation: Metallomics. 2012 Aug;4(9):899-909
references.pmid: 22700084
references.citation: Nat Rev Microbiol. 2012 Jul 16;10(8):525-37
references.pmid: 22796883
references.citation: Nat Rev Microbiol. 2009 May;7(5):355-66
references.pmid: 19369951
references.citation: Mol Microbiol. 2010 Sep;77(5):1096-110
references.pmid: 20624225
references.citation: Curr Med Chem. 2005;12(10):1161-208
references.pmid: 15892631
references.citation: Agents Actions. 1982 Jul;12(3):303-7
references.pmid: 7136956
references.citation: Rev Environ Health. 2006 Jul-Sep;21(3):153-215
references.pmid: 17243347
references.citation: Am J Clin Nutr. 1998 May;67(5 Suppl):1064S-1068S
references.pmid: 9587153
references.citation: J Biol Chem. 2009 Dec 4;284(49):33949-56
references.pmid: 19808669
references.citation: J Immunol. 2005 Feb 1;174(3):1491-500
references.pmid: 15661908
references.citation: Cell Host Microbe. 2013 Mar 13;13(3):265-76
references.pmid: 23498952
references.citation: Nat Chem Biol. 2013 Mar;9(3):177-83
references.pmid: 23354287
references.citation: J Med Chem. 2012 Dec 13;55(23):10448-59
references.pmid: 23170953
references.citation: J Am Chem Soc. 2011 Apr 27;133(16):6235-42
references.pmid: 21452832
references.citation: Curr Med Chem. 2005;12(18):2163-75
references.pmid: 16101497
references.citation: Biochem J. 2012 May 15;444(1):51-7
references.pmid: 22369063
references.citation: Appl Environ Microbiol. 2011 Mar;77(5):1541-7
references.pmid: 21193661
references.citation: Mol Microbiol. 2010 Dec;78(5):1246-58
references.pmid: 21091508
references.citation: Appl Environ Microbiol. 2010 Jan;76(1):150-60
references.pmid: 19880638
references.citation: Cell Host Microbe. 2012 Feb 16;11(2):106-15
references.pmid: 22341460
references.citation: Fundam Appl Toxicol. 1991 Feb;16(2):249-56
references.pmid: 2055356
references.citation: Infect Immun. 2012 Nov;80(11):3776-85
references.pmid: 22890995
references.citation: J Biol Inorg Chem. 2010 Jan;15(1):3-14
references.pmid: 19774401
references.citation: Gut. 2013 Feb;62(2):209-19
references.pmid: 22345661
references.citation: Chembiochem. 2010 Jan 4;11(1):59-62
references.pmid: 19937900
references.citation: J Biol Chem. 2012 Apr 20;287(17):13549-55
references.pmid: 22389498
references.citation: Aust J Sci Res B. 1951 Aug;4(3):275-82
references.pmid: 14886274
references.citation: PLoS Pathog. 2012 Sep;8(9):e1002870
references.pmid: 22969422
references.citation: Breast Cancer Res. 2005;7(6):R897-908
references.pmid: 16280039