Therapeutics/Drugs

Michael Klemba of Virginia Polytechnic Institute and State University in the U.S. will identify anti-malarial compounds from the Malaria Box that function as inhibitors of the cytostomal endocytic pathway used by the malaria parasite P. falciparum to internalize host erythrocyte proteins. Characterizing the molecular mechanisms of this process could lead to the discovery of new anti-malarial compounds.

Daniel Irimia and Anh Hoang of Massachusetts General Hospital in the U.S. seek to develop a microfluidic device that can be used to screen anti-malarial drugs for the development of drug resistance with single cell resolution. The device will be validated using a subset of anti-malarial compounds from the Malaria Box. The ability to monitor single cells for resistance will greatly reduce the time needed to screen drugs for acquired resistance, allowing for much earlier and more accurate assessment of effective drugs to control and eradicate malaria.

Gabriel Nunez of the University of Michigan in the U.S. will investigate whether inhibiting intimin, a virulence factor protein of E. coli, can help clear the bacteria from infected patients. Intimin helps the pathogen adhere to intestinal epithelial cells to cause virulence, but if intimin is inhibited the pathogen will relocate to the intestinal lumen, where it can be outcompeted by commensal bacteria.

Egil Lien with collaborators Beth McCormick and Mike Brehm of the University of Massachusetts Medical School in the U.S. will evaluate two mouse models for studying human typhoid fever. Typhoid fever is a major cause of environmental enteric dysfunction, which is associated with significant morbidity and mortality particularly in young children from developing countries. The causative Salmonella bacterium does not normally infect mice, hindering the development of mouse models for testing new treatments and vaccines.

Cirle Warren of the University of Virginia in the U.S. will develop a three dimensional cell culture model (organoid) of the human intestine to study diarrheal diseases. They will build the organoids in a bioreactor using three intestinal cell types, and test different scaffolds to simulate the complex cellular and structural architecture of the human gut. The organoids will then be infected with Cryptosporidium, a common cause of diarrhea in developing countries, and analyzed for altered structural and molecular characteristics to gain insight into the host infection response.

James Nataro of the University of Virginia in the U.S. is developing new mouse models of environmental enteric dysfunction (EED) to explore how enteric pathogens commonly found among children in developing countries can affect intestinal function and cause growth retardation. In Phase I, they developed mouse models for five of the common pathogens and found that, as in humans, malnutrition (protein or zinc deficiency) enhanced the severity of infection, associated growth retardation, or the presence of intestinal inflammation.

Sanjiban Banerjee and Sambuddha Ghosh at AbGenics LifeSciences Pvt. Ltd in India will develop a new method to treat intestinal worm (helminth) infections using modified probiotic strains of the bacterium Lactobacillus. Lactobacillus, which can live in the human gut, will be modified to produce stable RNA molecules selected to target specific helminth genes and ultimately destroy the parasite, thereby curing the infection. Because Lactobacillus colonizes the gut, it can be used as a long-term treatment for multiple helminth infections.

Danae Schulz and Erik Debler of Rockefeller University in the U.S. will test whether a drug that was originally developed to treat cancer and heart disease can also kill trypanosomes, which are parasites that cause African trypanosomiasis in humans and cattle. Repurposing a drug already approved for a different disease is highly cost-effective as expensive human safety trials are already complete. This particular drug is a bromodomain inhibitor that interferes with the structure of chromatin, and they have shown that it destroys trypanosomes grown in vitro.

Liam Morrison and Ivan Morrison of the Roslin Institute, University of Edinburgh in the United Kingdom will develop a new type of drug for treating diseases in animals and humans caused by African trypanosomes, which cause significant disease in sub-Saharan Africa. African trypanosomes evade the host immune system by varying their surface proteins, which can be recognized by conventional antibodies, precluding the development of an effective vaccine.

Catherine Tuleu of University College London in the United Kingdom will develop a rectal formulation of the antibiotic amoxicillin tailored specifically for children with pneumonia particularly in developing countries that can be stored long-term in hot climates. Suppositories are easy to administer, and avoid the bad taste of the antibiotic or the need to swallow a tablet, which is often difficult for children. They have already characterized several suppository bases and will test different excipients to provide stability at high temperatures.