Sensitivity of Trypanosomes to Metabolic Inhibitors*

Abstract

IntroductionTrypanosomiasis in its various forms, despite concerted international efforts for half a century, continues to make a serious impact upon the socioeconomic development of large parts of Africa and Central and South America.While human trypanosomiasis is presently under fairly good control in Africa, constant vigilance is essential as outbreaks can occur with sudden and explosive force when socioecologic factors a r e favorable.A dramatic example of the precarious nature of the present containment of sleeping sickness on the African continent is provided by the recent outbreak of the disease in the Nyanza region of Kenya.1After surveying available data on the incidence of trypanosomiasis in African livestock during the past two decades, Williamson2 concluded that "in animal disease in Africa, trypanosomiasis clearly constitutes a problem of the first magnitude." When it is realized that more than four million square miles in Africa, a mostly fertile land mass l a r g e r than the United States, a r e denied to efficient animal husbandry and the associated needs of millions of people because of veterinary trypanosomiases,3 the accuracy of Williamson's conclusion can be fairly appreciated.Human trypanosomiasis in South and Central America remains a formidable public health problem a s Chagas' disease, which i s very serious and also quite prevalent, thus far has no curative treatment available. It has been estimated4 that approximately seven million people in the Western Hemisphere harbor Trypanosoina C M Z~, while an additional thirty million are exposed to a high risk of infection.Several approaches to the control and even eradication of trypanosomiases a r e possible. Since all but one species of trypanosomes undergo cyclic development in, and/or a r e transmitted mechanically by, insects, vector destruction would interrupt transmission and lead eventually to elimination of the reservoir of infective cases. While active vector eradication programs a r e presently in progress in endemic areas, the immensity of the t r a c t s to be covered and the expense of chemical, biological, o r environmental control methods make this approach impracticable. Trypanosomes require a constantly supplied exogenous source of energy to maintain their characteristic motility and high synthetic capacity.12 Of all aspects of trypanosomal metabolism, those pathways by which glucose as well as certain other hexosesandglycerolare catabolized to yield energy and smaller carbon-chain derivatives a r e the most diverse among the different morphologic groups.All species seem to possess a functional Emden-Meyerhof pathway for phosphorylative glycolysis,l3-15 but members of the brucei and congolense groups produce proportionately l e s s lactate than do members of the uivax and lewisi-cruzi groups. 13 The presence of an operative hexosemonophosphate oxidative pathway has been established in Trypanosoma equiperdum 16 and in the culture form of T. cruzi. 17,18 On the other hand, Ryley19 found marked glucose-6-phosphate dehydrogenase ...