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 #
5R01AI056189-09
Application #
8461648
Study Section
Drug Discovery and Mechanisms of Antimicrobial Resistance Study Section (DDR)
Program Officer
Rogers, Martin J
Project Start
2005-04-01
Project End
2014-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
9
Fiscal Year
2013
Total Cost
$386,949
Indirect Cost
$117,365
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
Dementiev, Alexey; Board, Jason; Sitaram, Anand et al. (2016) The pesticidal Cry6Aa toxin from Bacillus thuringiensis is structurally similar to HlyE-family alpha pore-forming toxins. BMC Biol 14:71
Durmaz, Evelyn; Hu, Yan; Aroian, Raffi V et al. (2015) Intracellular and Extracellular Expression of Bacillus thuringiensis Crystal Protein Cry5B in Lactococcus lactis for Use as an Anthelminthic. Appl Environ Microbiol 82:1286-94
Wu, Chia-Chen; Hu, Yan; Miller, Melanie et al. (2015) Protection and Delivery of Anthelmintic Protein Cry5B to Nematodes Using Mesoporous Silicon Particles. ACS Nano 9:6158-67
Schwarz, Erich M; Hu, Yan; Antoshechkin, Igor et al. (2015) The genome and transcriptome of the zoonotic hookworm Ancylostoma ceylanicum identify infection-specific gene families. Nat Genet 47:416-22
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
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
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
Hui, Fan; Scheib, Ulrike; Hu, Yan et al. (2012) Structure and glycolipid binding properties of the nematicidal protein Cry5B. Biochemistry 51:9911-21
Hu, Yan; Aroian, Raffi V (2012) Bacterial pore-forming proteins as anthelmintics. Invert Neurosci 12:37-41

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