Action of deferoxamine against Pneumocystis carinii

We found earlier that deferoxamine (DFO), a drug used for treatment of iron overload, is active against a rat model of Pneumocystis carinii pneumonia (PCP). We had assumed a mode of action by deprivation of nutritional iron; however, data here show that DFO penetrates P. carinii, causing irreversibl e damage, thus indicating a different mode of action. Penetration was demon strated by showing DFO uptake by high-pressure liquid chromatography analys is. By using calcein-AM as an indicator, exposure to DFO was shown to cause a reduction in P. carinii cytoplasmic free iron. Exposure to greater than or equal to 100 muM DFO for greater than or equal to8 h in vitro caused gro wth to cease and cell numbers to decline over several days. This direct and irreversible damage to P. carinii led to the prediction that infrequent de livery of DFO to the lungs via an aerosol would be an effective treatment i n the animal model of PCP. This prediction was confirmed by demonstrating t hat a once-a-week aerosol treatment of rats was 100% effective both as a pr ophylactic and as a curative treatment in a rat model of PCP.