title: 8-Hydroxyquinolines Are Boosting Agents of Copper-Related Toxicity in Mycobacterium tuberculosis.
abstract: Copper (Cu) ions are likely the most important immunological metal-related toxin utilized in controlling bacterial infections. Impairment of bacterial Cu resistance reduces viability within the host. Thus, pharmacological enhancement of Cu-mediated antibacterial toxicity may lead to novel strategies in drug discovery and development. Screening for Cu toxicity-enhancing antibacterial molecules identified 8-hydroxyquinoline (8HQ) to be a potent Cu-dependent bactericidal inhibitor of Mycobacterium tuberculosis The MIC of 8HQ in the presence of Cu was 0.16 μM for replicating and nonreplicating M. tuberculosis cells. We found 8HQ's activity to be dependent on the presence of extracellular Cu and to be related to an increase in cell-associated labile Cu ions. Both findings are consistent with 8HQ acting as a Cu ionophore. Accordingly, we identified the 1:1 complex of 8HQ and Cu to be its active form, with Zn, Fe, or Mn neither enhancing nor reducing its Cu-specific action. This is remarkable, considering that the respective metal complexes have nearly identical structures and geometries. Finally, we found 8HQ to kill M. tuberculosis selectively within infected primary macrophages. Given the stark Cu-dependent nature of 8HQ activity, this is the first piece of evidence that Cu ions within macrophages may bestow antibacterial properties to a Cu-dependent inhibitor of M. tuberculosis In conclusion, our findings highlight the metal-binding ability of the 8-hydroxyquinoline scaffold to be a potential focus for future medicinal chemistry and highlight the potential of innate immunity-inspired screening platforms to reveal molecules with novel modes of action against M. tuberculosis.
authors.affiliation: Department of Medicine, Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Santosh
authors.initials: S
authors.lastname: Shah
authors.affiliation: Department of Medicine, Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Alex G
authors.initials: AG
authors.lastname: Dalecki
authors.affiliation: Department of Chemistry, Kansas State University, Manhattan, Kansas, USA.
authors.forename: Aruni P
authors.initials: AP
authors.lastname: Malalasekera
authors.affiliation: Department of Medicine, Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Cameron L
authors.initials: CL
authors.lastname: Crawford
authors.affiliation: Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Michalek
authors.affiliation: Department of Medicine, Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Olaf
authors.initials: O
authors.lastname: Kutsch
authors.affiliation: Department of Medicine, Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Jim
authors.identifier: 0000-0002-6873-6052
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Chemistry, Kansas State University, Manhattan, Kansas, USA.
authors.forename: Stefan H
authors.initials: SH
authors.lastname: Bossmann
authors.affiliation: Department of Medicine, Division of Infectious Diseases, University of Alabama at Birmingham, Birmingham, Alabama, USA fwolsche@uab.edu.
authors.forename: Frank
authors.initials: F
authors.lastname: Wolschendorf
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D056831:Coordination Complexes / Q000494:pharmacology; D003300:Copper / Q000737:chemistry / Q000494:pharmacology*; D004195:Disease Models, Animal; D004357:Drug Synergism; D005260:Female; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000382:microbiology; D008810:Mice, Inbred C57BL; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000472:pathogenicity; D015125:Oxyquinoline / Q000737:chemistry / Q000494:pharmacology*; D014376:Tuberculosis / Q000188:drug therapy
chemical_list: D000995:Antitubercular Agents; D056831:Coordination Complexes; D015125:Oxyquinoline; D003300:Copper