Many parasites have unusual basic cellular and molecular processes that, if clearly understood, can provide leads to highly selective therapy for the diseases they cause. A major research objective is discovering and characterizing unique aspects of the cell biology and biochemistry of two particular parasites: 1) Trypanosoma brucei ssp., or African trypanosomes, which cause African sleeping sickness in humans and a related disease in animals and 2) Pneumocystis carinii which causes the most common opportunistic infection associated with AIDS. Ultimately, we will exploit these aspects to design useful tools that will treat disease caused by these pathogens.

Recently we demonstrated that the mitochondrial terminal oxidase of the infectious stage of African trypanosomes is a noncytochrome ubiquinol:oxygen-oxidoreductase. We call this the 3trypanosome alternative oxidase2 or TAO because of the similarity we have observed to alternative oxidases of plants. We have synthesized a series of TAO inhibitors some of which allow us to cure infected mice. We have cloned the TAO gene and manipulated bacteria so as force them to be dependent on the TAO thus producing a system allowing protein structure/function studies. Since the response to plant and trypanosome alternative oxidases to inhibitors differ, work is underway building and comparing chimeras of alternative oxidases with the goal of better defining the optimal inhibitor structure for drug activity against the TAO.

We are studying polyamine biosynthesis and iron metabolism of P. carinii and we have proven both to be valid drug targets. Our work has demonstrated that P. carinii is very sensitive to interruption of polyamine biosynthesis. While host cells can compensate by downregulating polyamine degradation,P. carinii cannot so they rapidly become depleted of these small but essential cations when biosynthesis is blocked. We are exploring the genetic and physiological basis for this vulnerability. Because we have found that iron-binding chemicals (iron chelators) are therapeutic in an animal model of P. carinii pneumonia, we are researching the basis for this activity. Our recent improvements in the culture of P. carinii are proving to be very helpful for work with this parasite.