Abstract
Heme, an iron-bound cyclic tetrapyrrole, is an essential nutrient for virtually all living organisms, by serving as a prosthetic group in hemoproteins that are involved in many cellular activities, such as diatomic gas transport and detection, mitochondrial respiration, and detoxification in peroxisome. Microbial pathogens can acquire heme by de novo synthesis and incorporation of exogenous heme or heme biosynthetic intermediates1,2. Intracellular pathogenic microbes switch their heme resources by adapting the fluctuation of heme availability during the change of their replicative environment through infections2. Here, we show that the Toxoplasma gondii, an obligate intracellular human pathogen, encodes an active de novo heme biosynthetic pathway for heme supply. Genetical and chemical manipulation of this pathway revealed that T. gondii essentially requires its de novo heme production for its intracellular growth and pathogenesis. Revisit of tetrapyrrole synthesis inhibitors used in weed control identified oxadiazon as an inhibitor of Toxoplasma growth. Two derivatives synthesized in this study showed improved efficacies by 15- to 25-fold compared to oxadiazon, providing evidence that the interference in the de novo heme production in Toxoplasma is a potential therapeutic strategy to control infection. Additionally, due to its tractable genetics, T. gondii has been used as a model for studying the biology of apicomplexan parasites3. Thus, our study can serve as a model to help understand heme metabolism in other pathogenic apicomplexans.