Intestinal parasitic roundworms, most notably hookworms, whipworms, and Ascaris, infect over 2 billion people in tropical countries-more than 1.5X the populations of North American and Europe combined. These parasites are the leading cause of disease burden in school-aged children worldwide, with infections leading to anemia, malnutrition, growth stunting, cognitive and learning defects, school absenteeism, and reduced future earns. These parasites also exact a heavy toll on pregnant women and on adults by weakening their bodies and immune systems. Few treatment options exist. All have incomplete efficacy, and concerns about parasite resistance are mounting. New anti-roundworm drugs are urgently needed. We have pioneered the development of Bacillus thuringiensis (Bt) Cry proteins that kill roundworms. Bt is natural soil bacterium harmless to humans but lethal to insects. We proved it is lethal to roundworms as well. The work here shows that the Bt protein Cry5B can cure an intestinal roundworm infection in a small mammal 3X better than the current leading drug. The research proposed is designed to optimize the therapeutic potential of Cry5B by formulating it to protect it against the mammalian digestive tract, by developing new means of purifying it, and by studying its combinatorial characteristics with known anti- roundworm drugs. Tests of Cry5B's effectiveness alone and in drug combinations will be performed using the free-living roundworm C. elegans, the mouse parasite H. bakeri, and close models of all three human parasite classes. Basic research detailing the genetic and transcriptional interaction between Cry5B and roundworms will be undertaken as well. The ultimate objective of this work is to develop an anti-roundworm drug or drug combination that is order(s) of magnitude better than any currently out there and that is highly recalcitrant to parasite resistance.

Public Health Relevance

Intestinal parasitic roundworms infect ~2 billion people, placing a tremendous health burden on the poorest peoples and trapping them in poverty. Current drugs are incompletely effective, and there are growing concerns the parasites are becoming resistant to them. Here we propose to develop a new drug we discovered that is made by a natural soil bacterium (which is harmless to humans) and that appears to be a very potent anti-roundworm compound with activity greater than any currently available.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI056189-08
Application #
8260243
Study Section
Drug Discovery and Mechanisms of Antimicrobial Resistance Study Section (DDR)
Program Officer
Rogers, Martin J
Project Start
2003-07-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
8
Fiscal Year
2012
Total Cost
$411,649
Indirect Cost
$124,856
Name
University of California San Diego
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Somvanshi, Vishal S; Ellis, Brian L; Hu, Yan et al. (2014) Nitazoxanide: nematicidal mode of action and drug combination studies. Mol Biochem Parasitol 193:1-8
Hu, Yan; Ellis, Brian L; Yiu, Ying Y et al. (2013) An extensive comparison of the effect of anthelmintic classes on diverse nematodes. PLoS One 8:e70702
Urban Jr, Joseph F; Hu, Yan; Miller, Melanie M et al. (2013) Bacillus thuringiensis-derived Cry5B has potent anthelmintic activity against Ascaris suum. PLoS Negl Trop Dis 7:e2263
Hu, Yan; Miller, Melanie M; Derman, Alan I et al. (2013) Bacillus subtilis strain engineered for treatment of soil-transmitted helminth diseases. Appl Environ Microbiol 79:5527-32
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Balla, Keir M; Lugo-Villarino, Geanncarlo; Spitsbergen, Jan M et al. (2010) Eosinophils in the zebrafish: prospective isolation, characterization, and eosinophilia induction by helminth determinants. Blood 116:3944-54
Hu, Yan; Georghiou, Sophia B; Kelleher, Alan J et al. (2010) Bacillus thuringiensis Cry5B protein is highly efficacious as a single-dose therapy against an intestinal roundworm infection in mice. PLoS Negl Trop Dis 4:e614
Hu, Yan; Platzer, Edward G; Bellier, Audrey et al. (2010) Discovery of a highly synergistic anthelmintic combination that shows mutual hypersusceptibility. Proc Natl Acad Sci U S A 107:5955-60

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