Pantothenate Utilization by Plasmodium as a Target for Antimalarial Chemotherapy

C.      Spry; D.A.      van Schalkwyk; E.      Strauss; K.J.      Saliba

Abstract

In the absence of an effective vaccine against malaria suitable for widespread deployment, the control of this lethal infectious disease relies heavily on antimalarial chemotherapies. The most virulent of the parasites that cause malaria (Plasmodium falciparum) has, however, developed resistance to all antimalarial agents in clinical use, and there is a desperate need for new antimalarial agents that target previously unexploited parasite processes. P. falciparum requires an extracellular supply of pantothenate to support its proliferation during the erythrocytic stage of its development in humans. This requirement highlights the mechanisms involved in the utilization (uptake and metabolism) of pantothenate as potential targets for chemotherapeutic attack. Here we review the evidence demonstrating pantothenate to be an essential nutrient for P. falciparum and data from studies investigating whether this parasite has the capacity to utilize exogenous supplies of the cofactor (coenzyme A; CoA) for which pantothenate serves as a precursor. The results of recent studies aimed at characterizing the mechanisms by which pantothenate is taken up by the P. falciparum-infected erythrocyte and intracellular parasite, and metabolized to CoA, are described. The unique properties that may be exploited to develop selective inhibitors of pantothenate utilization by P. falciparum-infected erythrocytes are highlighted. The molecular identities of P. falciparum pantothenate transporter(s) and CoA biosynthesis enzymes remain unconfirmed. We consider the possible identities, and emphasize the importance of generating these proteins in pure, functionally-active form. The tools currently available for identifying inhibitors of pantothenate utilization that may be potent antiplasmodial agents are also discussed.

Keywords: Pantothenate, coenzyme A, malaria, Plasmodium, drug target, vitamin, metabolism, biosynthesis