Recombinant Paraprobiotics as a New Paradigm for Treating Gastrointestinal Nematode Parasites of Humans
Open Access
- 28 February 2021
- journal article
- research article
- Published by American Society for Microbiology in Antimicrobial Agents and Chemotherapy
- Vol. 65 (3)
- https://doi.org/10.1128/AAC.01469-20
Abstract
Gastrointestinal nematodes (GINs) of humans, e.g., hookworms, negatively impact childhood growth, cognition, nutrition, educational attainment, income, productivity, and pregnancy. Hundreds of millions of people are targeted with mass drug administration (MDA) of donated benzimidazole anthelmintics. However, benzimidazole efficacy against GINs is suboptimal, and reduced/low efficacy has been seen. Developing an anthelmintic for human MDA is daunting: it must be safe, effective, inexpensive, stable without a cold chain, and massively scalable. Bacillus thuringiensis crystal protein 5B (Cry5B) has anthelmintic properties that could fill this void. Here, we developed an active pharmaceutical ingredient (API) containing B. thuringiensis Cry5B compatible with MDA. We expressed Cry5B in asporogenous B. thuringiensis during vegetative phase, forming cytosolic crystals. These bacteria with cytosolic crystals (BaCC) were rendered inviable (inactivated BaCC [IBaCC]) with food-grade essential oils. IBaCC potency was validated in vitro against nematodes. IBaCC was also potent in vivo against human hookworm infections in hamsters. IBaCC production was successfully scaled to 350 liters at a contract manufacturing facility. A simple fit-for-purpose formulation to protect against stomach digestion and powdered IBaCC were successfully made and used against GINs in hamsters and mice. A pilot histopathology study and blood chemistry workup showed that five daily consecutive doses of 200 mg/kg body weight Cry5B IBaCC (the curative single dose is 40 mg/kg) was nontoxic to hamsters and completely safe. IBaCC is a safe, inexpensive, highly effective, easy-to-manufacture, and scalable anthelmintic that is practical for MDA and represents a new paradigm for treating human GINs.Keywords
Funding Information
- HHS | NIH | National Institute of Allergy and Infectious Diseases (R01AI056189, R01AI50866)
- USDA | National Institute of Food and Agriculture (2015-11323)
This publication has 81 references indexed in Scilit:
- Bacillus thuringiensis-derived Cry5B Has Potent Anthelmintic Activity against Ascaris suumPLoS Neglected Tropical Diseases, 2013
- Association between Response to Albendazole Treatment and β-Tubulin Genotype Frequencies in Soil-transmitted HelminthsPLoS Neglected Tropical Diseases, 2013
- Increased Birth Weight Associated with Regular Pre-Pregnancy Deworming and Weekly Iron-Folic Acid Supplementation for Vietnamese WomenPLoS Neglected Tropical Diseases, 2012
- Low Efficacy of Single-Dose Albendazole and Mebendazole against Hookworm and Effect on Concomitant Helminth Infection in Lao PDRPLoS Neglected Tropical Diseases, 2012
- In Vitro and In Vivo Efficacy of Monepantel (AAD 1566) against Laboratory Models of Human Intestinal Nematode InfectionsPLoS Neglected Tropical Diseases, 2011
- The immunomodulatory properties of probiotic microorganisms beyond their viability (ghost probiotics: proposal of paraprobiotic concept)Genes & Nutrition, 2011
- Discovery of a highly synergistic anthelmintic combination that shows mutual hypersusceptibilityProceedings of the National Academy of Sciences of the United States of America, 2010
- Bacillus thuringiensis Cry5B Protein Is Highly Efficacious as a Single-Dose Therapy against an Intestinal Roundworm Infection in MicePLoS Neglected Tropical Diseases, 2010
- A purified Bacillus thuringiensis crystal protein with therapeutic activity against the hookworm parasite Ancylostoma ceylanicumProceedings of the National Academy of Sciences of the United States of America, 2006
- Occurrence of Natural Bacillus thuringiensis Contaminants and Residues of Bacillus thuringiensis -Based Insecticides on Fresh Fruits and VegetablesApplied and Environmental Microbiology, 2006