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.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Drug Discovery and Mechanisms of Antimicrobial Resistance Study Section (DDR)
Program Officer
Rogers, Martin J
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Diego
Schools of Arts and Sciences
La Jolla
United States
Zip Code
Tyagi, Rahul; Maddirala, Amarendar Reddy; Elfawal, Mostafa et al. (2018) Small Molecule Inhibitors of Metabolic Enzymes Repurposed as a New Class of Anthelmintics. ACS Infect Dis 4:1130-1145
Hu, Yan; Nguyen, Thanh-Thanh; Lee, Alice C Y et al. (2018) Bacillus thuringiensis Cry5B protein as a new pan-hookworm cure. Int J Parasitol Drugs Drug Resist 8:287-294
Papaiakovou, Marina; Pilotte, Nils; Baumer, Ben et al. (2018) A comparative analysis of preservation techniques for the optimal molecular detection of hookworm DNA in a human fecal specimen. PLoS Negl Trop Dis 12:e0006130
Chen, Huan-Da; Kao, Cheng-Yuan; Liu, Bang-Yu et al. (2017) HLH-30/TFEB-mediated autophagy functions in a cell-autonomous manner for epithelium intrinsic cellular defense against bacterial pore-forming toxin in C. elegans. Autophagy 13:371-385
Noon, Jason B; Aroian, Raffi V (2017) Recombinant subunit vaccines for soil-transmitted helminths. Parasitology 144:1845-1870
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. (2016) Intracellular and Extracellular Expression of Bacillus thuringiensis Crystal Protein Cry5B in Lactococcus lactis for Use as an Anthelminthic. Appl Environ Microbiol 82:1286-94
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
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
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

Showing the most recent 10 out of 25 publications