title: Conditional lethality of the diprotic weak bases chloroquine and quinacrine against Cryptococcus neoformans.
abstract: Chloroquine at 10 microM enhances the activity of macrophages against Cryptococcus neoformans but does not directly inhibit cryptococcal growth. The antifungal activity of higher chloroquine concentrations likely to be found within the acidic cryptococcal phagosome was tested. Concentrations of >/=30 microM inhibited cryptococcal growth, and there was fungal killing at concentrations of >/=100 microM. Activity was dependent on physiologic temperature and pH. Quinacrine was 50-fold more active than chloroquine, and concentrations as low as 100 nM enhanced macrophage anticryptococcal activity. Quinacrine was concentrated within a vacuolar system within the fungal cell and highly concentrated within intracellular C. neoformans. Ammonium chloride and bafilomycin A both inhibited cryptococcal growth, suggesting that the activity of chloroquine and quinacrine may in part be due to disruption of pH-dependent processes. These findings add to the known spectrum of activity of chloroquine and quinacrine. These, and related compounds, may have utility for the treatment of cryptococcosis.
authors.affiliation: Department of Infectious Diseases, Division of Cellular and Molecular Sciences, St. George's Hospital Medical School, London SW17 ORE, United Kingdom. tharriso@sghms.ac.uk
authors.forename: T S
authors.initials: TS
authors.lastname: Harrison
authors.forename: G E
authors.initials: GE
authors.lastname: Griffin
authors.forename: S M
authors.initials: SM
authors.lastname: Levitz
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000935:Antifungal Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002738:Chloroquine / Q000494:pharmacology*; D003455:Cryptococcus neoformans / Q000187:drug effects* / Q000378:metabolism; D004338:Drug Combinations; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018942:Macrolides; D008826:Microbial Sensitivity Tests; D011796:Quinacrine / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D018942:Macrolides; C057620:bafilomycin A; D002738:Chloroquine; D011796:Quinacrine