INHIBITION OF GROWTH OF HISTOPLASMA-CAPSULATUM YEAST-CELLS IN HUMAN MACROPHAGES BY THE IRON CHELATOR VUF-8514 AND COMPARISON OF VUF-8514 WITH DEFEROXAMINE

Histoplasma capsulatum requires intracellular iron to survive and mult iply within human and murine macrophages (M phi). Thus, iron chelators may be useful compounds in the treatment of histoplasmosis. In the pr esent study we compared the efficacies of five different iron chelator s with deferoxamine (DEF) for their capacity to inhibit the growth of H. capsulatum yeast cells in culture medium and within human M phi. Of the agents tested, only one, VUF 8514, a 2,2'-bipyridyl analog, was f ound to be effective. VUF 8514 inhibited the growth of yeast cells in tissue culture medium and within M phi in a dose-response fashion. In tissue culture medium, the 50% effective dose (ED(50)) of VUF 8514 was 30 nM and the ED(50) of DEF was 1 mM. In human M phi, the ED(50) of V UF 8514 was 520 nM and the ED(50) of DEF was 4 mM. Thus, VUF 8514 was effective at a concentration 7.7 x 10(3)-fold lower than DEF in inhibi ting the growth of yeast cells in M phi. Inhibition of the intracellul ar growth of yeast cells by VUF 8514 was reversed by holotransferrin a nd iron nitriloacetate, an iron compound that is soluble at neutral to alkaline pH. Thus, VUF 8514 inhibits the intracellular growth of yeas t cells by acting as an iron chelator rather than through its capacity as a weak base. These data suggest that the hydroxamic acid sideropho re of H. capsulatum yeast cells competes successfully for iron against some iron chelators but not others and that VUF 8514 may be a potenti al therapeutic agent for the treatment of histoplasmosis.