Therapeutics/Drugs

Manoj Duraisingh of the Harvard School of Public Health in the U.S. will use RNAi screening to identify critical determinants in human red blood cells (erythrocytes) that are required for invasion and growth of the malaria parasite, Plasmodium falciparum. In this project's Phase I research, Duraisingh's group developed a RNAi- based approach for genetic analysis of the erythrocyte in vitro, and demonstrated that the major surface protein Glycophorin A is required for efficient invasion by some strains of P. falciparum.

Antimicrobial peptides (AMPs) are essential components of the innate immune system that provides resistance to a variety of pathogenic organisms by selectively lysing, or bursting, cellular membranes of invading pathogens. Doron Greenbaum of the University of Pennsylvania in the U.S. will test whether small molecules that mimic the natural AMPs can selectively kill the parasite that causes malaria. Such an approach could reduce costs of production as well as limit the emergence of drug resistance.

David A. Spiegel of Yale University in the U.S. will pursue an antibiotic strategy called "biosynthetic immunotargeting." Streptococcus pneumoniae will be fed small molecules which they will incorporate into their cell walls. These small molecules contain an epitope recognized by antibodies in the human bloodstream, leading to immune clearance independent of bacterial antigens, representing a unique, resistance-free approach to pneumococcal disease.

Marcus Horwitz and colleagues at UCLA in the U.S. will develop and test a novel drug delivery system in which nanoparticles loaded with anti-TB drugs selectively target macrophages, and release the drugs intracellularly via a pH-dependent gate, allowing delivery of high concentrations on antibiotics into the host cells for Mycobacterium tuberculosis.

Gerald R. Smith of the Fred Hutchinson Cancer Research Center in the U.S. seeks to identify inhibitors of a bacterial DNA repair enzyme that allows tuberculosis to mutate. Identifying these inhibitors could lead to therapies that kill bacteria and limit drug resistance.

Bongkoch Tarnchompoo of the National Center for Genetic Engineering and Biotechnology in Thailand will attempt to develop and test a novel drug that binds to the two pathways used by the DHFR enzyme in P. falciparum to mutate. By tethering these active sites, the dual-binding drug will suppress the development of resistance to anti-malarial drugs.

Reto Brun (Swiss Tropical and Public Health Institute) and Isabel Roditi (University of Bern) in Switzerland seek to identify small molecules that prematurely induce African trypanosomes, which are parasites that cause fatal sleeping sickness, to differentiate into the life stages necessary for transmission of the parasite. Forcing this transformation within the mammalian host could be the basis for new methods to kill trypanosomes, and this concept might be applied to other vector-borne disease .

To optimize the effectiveness of current anti-tuberculosis drugs, Boitumelo Semete of the CSIR in South Africa will work with collaborators to develop "sticky nanoparticles" that specifically attach to TB-infected cells. Once taken in by these cells, the nanoparticles will slowly degrade, releasing the anti-TB drugs and killing the bacteria. With this novel drug delivery system, the team aims to improve the bioavailability of the current therapies, with the possibility of shortening the treatment period for TB as well as reduce drug side effects.

Oladele Akogun of the Common Heritage Foundation in Nigeria seeks to develop a "fever kit" for use among nomadic populations to help them accurately diagnose and treat fevers in a way that reduces mortality and drug resistance. The device will be equipped with simple diagnostic tools and prerecorded treatment instructions in the native language to help nomadic caregivers distinguish between malaria and other causes of fevers, and will also contain drug treatments appropriate to the diagnosed illness.

Because tuberculosis manipulates host cells to resist the immune response and current drug therapies, Nigel Savage of Leiden University Medical Center in the Netherlands will utilize RNAi analysis to identify the essential pathways used by the bacteria to modify its host cell. By discovering these pathways, novel therapies can be developed to counteract this host manipulation without directly targeting the pathogen and causing the development of resistance.