The long term objective of this project is to identify and to study novel chemotherapeutic approaches to the control of leishmanial and American trypanosomal infections of substantial medical importance, by exploiting knowledge that aspects of the lipid biochemistry of the responsible trypanosomatid flagellates are characteristic of fungi and other plants and not of vertebrates. The immediate specific aims to realize this objective are to investigate the: a) sterol, phospholipid and glycosphingolipid biochemistry of the life-cycle stages of representative leishmania species and Trypanosoma cruzi strains, b) perturbations of that biochemistry, and impairment of growth, cause by drugs targeted to specific enzymatic reactions, and c) mechanisms of action of the most effective of those drugs. Life-cycle stages are to be cultured within and without tissue cells exposed to drugs and radio- and stable isotopic tracers, and the consequences to growth and to lipid metabolism assessed by population enumeration, and by lipid analyses employing chromatographic (CC, TLC, HPLC, GLC), and spectrometric (GC/MS, 1H & 13C NMR, UV/VIS, liquid scintillation) methodologies. By these means, drugs active on enzymatic reactions unique to leishmanias and trypanosomes, or with properties different from those of analogous reactions in man, are to be identified, and their selective toxicities for the parasites and for host tissue cells established.
