Investigation of a shipworm endosymbiont compound with activity against the AIDS-associated pathogens Cryptosporidium and Toxoplasma

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 DESCRIPTION (provided by applicant): Cryptosporidium spp. and Toxoplasma gondii are opportunistic apicomplexan parasites that cause significant morbidity and mortality in immunocompromised people. New therapeutics to treat these parasites are a medical imperative. We have identified a compound produced by a mollusk symbiotic bacterium that inhibits intracellular growth of C. parvum and T. gondii without toxicity to the host cell. Shipworms are marine bivalve mollusks that burrow into and voraciously consume wood. Like most xylophagous animals, shipworms digest wood with the assistance of their symbiotic bacteria but in shipworms, the symbionts are housed within the cells of the gill and export cellulolytic enzymes out of the bacterial vacuole, out of the host cell, and into the lumen of the caecum where they effect digestion of the shipworm's woody diet. Despite the nutrient rich environment, the shipworm caecum lacks a bacterial community suggesting the presence of potent anti-microbial compounds. Shipworm symbionts have been shown to produce anti-microbial secondary metabolites in vivo and it is likely these compounds play a role in maintaining the nearly sterile environment of the caecum. We found that the shipworm gill endosymbiont, Teredinibacter turnerae, produces a compound that inhibits intracellular growth of C. parvum and T. gondii at nM levels in vitro and inhibits C. parvum infection in mice. This compound is also active against the related hemoparasite, Babesia bovis, suggesting a broad efficacy against apicomplexans. In this application, we will test the hypothesis that this compound targets a gene product or process common to T. gondii and C. parvum, and that this activity is effective in vivo. To test this hypothesis, we propose the following specific aim: Aim 1A - Identify the T. gondii and C. parvum infection processes targeted by the symbiont compound. We will evaluate the effect of the symbiont compound on specific parasite processes and test the compound against other apicomplexans, including Type II T. gondii tachyzoites and bradyzoites. Aim 1B - Identify the target of the symbiont compound's activity in C. parvum and T. gondii. We will employ both genetic and biochemical approaches to identify the gene products targeted by this compound. Aim 1C - Evaluate the efficacy of the symbiont compound against murine C. parvum infection. These experiments will provide the foundation for future studies involving target verification, structure-activity relationships, pharmacokinetic-pharmacodynamic evaluation and tests of efficacy in other animal models of C. parvum and T. gondii infection. Shipworm symbionts have never before been investigated for their potential to produce anti-parasitic compounds. Thus, these studies have tremendous potential to open up a new area of anti-parasitic drug discovery, holding the promise of new molecular targets for drug development, potentially with broad application to many intractable pathogens.