Fighting Protozoan Infections
In 1993, Milwaukee, Wisc., was gripped by a microscopic enemy that killed more than 100 people and sickened another 403,000 when it infiltrated the municipal water supply. Cryptosporidium parvum, a deadly water-borne pathogen, caused the largest waterborne disease outbreak to date in U.S. history. For two weeks, one of the two water treatment plants serving Milwaukee malfunctioned, causing residents to suffer from cramps, fever, diarrhea and dehydration. The root cause of the malfunction was never officially determined.
Currently, no drugs or vaccines exist to treat C. parvum infection. But biochemist Liz Hedstrom hopes to change that. She is leading groundbreaking research into drug targets that could help eradicate this deadly protozoan foe. Her research has generated one patent filing so far, with additional patents soon to follow, all with an eye to bringing to market new drugs to conquer C. parvum.
Listed as a potential agent for bioterrorism, C. parvum can survive outside a host for long periods in its environmentally stable spore (oocyst) stage and can cause severe gastrointestinal illness in humans. The pathogen is the organism most commonly isolated in immuno-compromised patients. Small children, pregnant women, and the elderly are also at risk of chronic and often fatal infection.
C. parvum produces spores that are highly resistant to water purification treatments, including chlorine-based disinfection. Infection rates soar when people ingest these oocytes, which then hatch in the small intestine and wreak havoc. The protozoan is the leading cause of diarrhea and malnutrition in developing countries.
Hedstrom and her collaborators have identified protozoan inosine-5’-monophosphate dehydrogenase (IMPDH), a key enzyme in the purine salvage pathway. Salvage pathways help recycle nucleotides (purine and pyrimidine) that are formed during degradation of RNA and DNA. Her research has shown that IMPDH inhibitors block parasitic proliferation in vivo.
Importantly, the C. parvum IMPDH has very different properties from that of the human enzyme, allowing the screening for inhibitors specifically against protozoan IMPDH. Leading a large-scale screen of a commercial library containing 44,000 compounds at the New England Regional Center of Excellence Biodefense and Emerging Infectious Diseases, in Cambridge, MA, Hedstrom discovered more than 50 new inhibitory target sites within the parasite enzyme.
Her group identified potent and highly selective small molecule inhibitors of C. parvum that effectively block the proliferation of the parasite in humans and mammals, making her research highly useful for the development of drug treatments to conquer C. parvum.
“Liz Hedstrom has gone beyond the basic biochemistry and has screened compounds that affect C. parvum, and we have patent claims on these compounds,” says Irene Abrams, executive director of the Office of Technology Licensing. “ I am very optimistic that the compounds may become a lead candidate for a drug, and we are currently looking for commercial partners to take these compounds in-house and continue their development.”
“We are looking forward to working with companies in developing novel drugs to treat cryptosporidiosis and prevent transmission. The team’s goal now,” Hedstrom explains, “is to achieve proof of concept in an animal model.”