Conditional lethality of the diprotic weak bases chloroquine and quinacrine against Cryptococcus neoformans

Chloroquine at 10 mu M enhances the activity of macrophages against Cryptoc occus neoformans but does not directly inhibit cryptococcal growth, The ant ifungal activity of higher chloroquine concentrations likely to be found wi thin the acidic cryptococcal phagosome was tested. Concentrations of greate r than or equal to 30 mu M inhibited cryptococcal growth, and there was fun gal killing at concentrations of greater than or equal to 100 mu M. Activit y was dependent on physiologic temperature and pH.z 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 intra cellular C. neoformans. Ammonium chloride and bafilomycin A both inhibited cryptococcal growth, suggesting that the activity of chloroquine and quinac rine may in part be due to disruption of pH-dependent processes. These find ings add to the known spectrum of activity of chloroquine and quinacrine, T hese, and related compounds, may have utility for the treatment of cryptoco ccosis.