Occidiofungin as a new lead against the enteric AIDS-OI cryptosporidium

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Project Summary The enteric protozoan Cryptosporidium is an AIDS-OI pathogen, a water-borne parasite that caused >100 deaths in the 1993 outbreak in Milwaukee, WI. Cryptosporidium is a biodefense category B agent, presenting a credible security threat. It is also one of the top few diarrheal agents that afflicts children in developing countries. However, no drugs are FDA-approved to treat cryptosporidiosis in AIDS patients. Nitazoxanide is the only drug approved for use in immune-competent individuals, whereas it is not fully effective. Therefore, there is a need to develop new anti-cryptosporidium drugs, particularly for AIDS patients and children. This project is developed based on recent observation that occidiofungin, a glycolipopeptide, possessed outstanding anti-cryptosporidium activity in vitro with limited cytotoxicity (EC50 = 120−138 nM vs. TC50 = ~1.0−2.5 μM). Occidiofungin is an amphipathic molecule, consisting of a hydrophilic body and a hydrophobic tail. It is nonabsorbable by the digestive system, and could be accumulated in the gastrointestinal tract. Because Cryptosporidium differs from other apicomplexans by its unique “epi-cytoplasmic” lifestyle (i.e., intracellular, but extra-cytoplasmic on the intestinal epithelia), a non-systemic drug with mucoadhesive property like occidiofungin has the advantage to act more effectively on the parasite. The strong preliminary data allows the team to build a central hypothesis that the non-systemic occidiofungin can serve as a novel structure for potentially developing new anti-cryptosporidium therapeutics. To test the hypothesis, the team will conduct in vivo experiments to achieve the following two specific aims: Aim 1 is to definitively verify the anti-cryptosporidium activity of occidiofungin two mouse models: an acute infection model in IL-12 knockout mice, and a newly developed chronic infection model in R2G2 mice. Aim 2 is to determine the gastrointestinal pharmacokinetics of occidiofungin, including its distributing kinetics in the luminal contents, mucus layers and mucosa among various GI segments, and its correlation with anti- cryptosporidium efficacy. Its mucoadhesive property in vitro will also be investigated. The long-term goal of the project is to explore non-systemic drugs for potential development of therapeutics against the enteric cryptosporidium. The completion of the two aims will ultimately determine whether occidiofungin can be pursued further as an anti-cryptosporidium lead, and justify next stage of investigation (e.g., lead optimization and formulation aimed to improve the mucoadhesive property, anti-parasitic efficacy, selectivity and safety). Data obtained in this project may also provide basis for exploring the potential of occidiofungin and its derivatives against other enteric parasites (such as Giardia and Entamoeba).