Parasitic Diseases | SACLab

NEGLECTED TROPICAL DISEASES (NTDS) - PARASITIC

Infectious diseases, such as malaria, diarrheal disease, and neglected tropical infections kill over 8 million people each year, (Global Burden of Disease 2015, Liu.L et al 2015). Our research interests are focused on biological evaluation of chemical compounds on key human parasites for drug discovery and clinically corroborating these compounds. Our lab currently focuses on parasitic diseases, such as malaria, cryptosporidiosis, and two major kinetoplastid diseases – human African trypanosomiasis (sleeping sickness), and Chagas disease.

MALARIA

Plasmodium is the causative agent of malaria, and is one of the major causes of death and illness in world. The World Health Organization estimates that 3.2 billion people are at risk of acquiring malaria, with 214 million cases occurring worldwide, resulting in 438,000 deaths, of which ninety percent occur in the African region. Plasmodium falciparum and Plasmodium vivax are the main etiological agents. New drugs with diverse modes of action are needed to combat resistance, block transmission, prevent infection, and reduce relapse. We have developed in vitro and in vivo high throughput assays to screen diverse chemical libraries against malarial parasite. Such compounds will be used in combination with current treatments to develop regimens that promote accessibility, compliance, and take into account the need of particularly vulnerable patients.

AFRICAN TRYPANOSOMIASIS (SLEEPING SICKNESS), CHAGAS DISEASE, AND LEISHMANIASIS

Kinetoplastid parasites include pathogens that cause human African trypanosomiasis (sleeping sickness), Chagas disease, and leishmaniasis. Together these diseases result in over 50,000 deaths each year worldwide. The kinetoplastids, including Trypanosoma and Leishmania species, are highly associated with poverty and are severely neglected for development of diagnostics, treatments, and vaccines. The challenges facing available drugs include toxicities, limited efficacy, and difficulties in administering them.

Our lab researchers working with collaborators involved in fatty acid metabolism and are in the early stages of developing a fast-acting, oral treatment specifically for human African trypanosomiasis and Chagas disease. So far, we have identified a novel class of compounds that are highly active in: (a) enzymatic activity assays against an enzyme, and (b) trypanocidal activity assays in axenic cultures of the parasite. The goal is to replace existing drugs, which are dosed intravenously and show significant toxicities. An improved oral regimen may support elimination of this disease.

CRYPTOSPORIDIOSIS

Cryptosporidium is a major cause of diarrheal disease in humans and animals. It became clinically first known as a causative agent of profuse and persistent diarrhea and morbidity in immunocompromised patients, particularly those with acquired immunodeficiency syndrome, and as a major cause of waterborne diarrheal disease in outbreaks in otherwise healthy individuals. More recently, large population studies have shown that Cryptosporidium is among the five leading causes of diarrheal disease in young children worldwide, underlining the urgency of addressing the medical needs posed by this parasite, particularly since current treatment options are severely limited.

We have developed a series of potent compounds with low cytotoxicity from an ongoing antibacterial project in our lab, focused on M. tuberculosis (Mtb). This structure-guided drug discovery project targeted biotin, the carboxyltransferase domain of acetyl CoA carboxylase (ACC). Sequence homology between the Mtb ACC-CT (Acetyl CoA carboxylase-carboxyltransferase) and C. parvum ortholog suggested significant overlap between the SAR (Structural Activity Relationship) of inhibitors for these two infectious agents. Indeed this is what we discovered when we tested several series of potent Mtb ACC inhibitors against C.parvum. Based on these initial results, medicinal chemistry efforts in our lab have successfully produced extremely potent compounds against animal models of cryptosporidiosis. In collaboration with University of Georgia and Washington State University, we have used animal models for Cryptosporodium drug discovery. These animal models brought about the identification of a potent and specific Crytosporodium ACC-CT inhibitor. We are expanding drug discovery efforts to identify novel agents to fight cryptosporidiosis.

Liu, L. et al. Global, regional, and national causes of under-5 mortality in 2000-15: an updated systematic analysis with implications for the Sustainable Development Goals. The Lancet. 2016.