Pantothenic acid biosynthesis in the parasite Toxoplasma gondii: a target for chemotherapy.

Sarmad N Mageed, Fraser Cunningham, Alvin Wei Hung, Hernani Leonardo Silvestre, Shijun Wen, Tom L Blundell, Chris Abell, Glenn A McConkey

Index: Antimicrob. Agents Chemother. 58(11) , 6345-53, (2014)

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Abstract

Toxoplasma gondii is a major food pathogen and neglected parasitic infection that causes eye disease, birth defects, and fetal abortion and plays a role as an opportunistic infection in AIDS. In this study, we investigated pantothenic acid (vitamin B5) biosynthesis in T. gondii. Genes encoding the full repertoire of enzymes for pantothenate synthesis and subsequent metabolism to coenzyme A were identified and are expressed in T. gondii. A panel of inhibitors developed to target Mycobacterium tuberculosis pantothenate synthetase were tested and found to exhibit a range of values for inhibition of T. gondii growth. Two inhibitors exhibited lower effective concentrations than the currently used toxoplasmosis drug pyrimethamine. The inhibition was specific for the pantothenate pathway, as the effect of the pantothenate synthetase inhibitors was abrogated by supplementation with pantothenate. Hence, T. gondii encodes and expresses the enzymes for pantothenate synthesis, and this pathway is essential for parasite growth. These promising findings increase our understanding of growth and metabolism in this important parasite and highlight pantothenate synthetase as a new drug target. Copyright © 2014, American Society for Microbiology. All Rights Reserved.