Evaluation of Carotenoid Biosynthesis as an Antimalarial Drug Target
Abstract
Malaria is one of the most devastating diseases and urgent health problems facing the world. Half of the global population is considered at risk of infection by Plasmodium malaria parasites, and hundreds of millions of people are infected annually by this virulent pathogen, resulting in hundreds of thousands of deaths. A broadly protective vaccine remains elusive, and parasite resistance to current antimalarial drugs continues to develop. Artemisinin combination therapies (ACTs) have been tremendously effective in combating multidrug-resistant malaria, but the recent identification of artemisinin-resistant parasites in Southeast Asia has raised pressing concerns that ACT potency is waning, which could lead to a resurgence in malaria deaths. Malaria is a major threat to U.S. military personnel serving in malaria endemic regions, especially Southeast Asia, the Middle East, and sub-Saharan Africa. According to the Medical Surveillance Monthly Report, there have been over 700 cases of malaria among U.S. Service members over the last decade. In addition, hundreds of thousands of troops serving in endemic areas are potentially exposed to multidrug-resistant malaria parasites and require effective prophylaxis to prevent infection. Although malaria cases among Service members stationed in the Middle East have diminished in recent years with force reductions in Iraq and Afghanistan, shifting military priorities to Southeast Asia could result in a resurgence in malaria cases due to multidrug-resistant parasites that will be difficult to treat with existing therapies. These concerns highlight the urgent need to define new drug targets and to develop novel antimalarial therapies that can combat this growing menace. The proposed studies directly address this urgent problem by seeking to identify new essential P. falciparum enzymes that are absent from human cells and can thus provide novel parasite-specific targets for development of next-generation antimalarial therapies with new mechanisms of action. This proposal elucidates carotenoid biosynthesis as a new parasite-specific metabolic pathway and will directly evaluate its essentiality for blood-stage parasites and thus test its potential to serve as a next-generation therapeutic target. Carotenoids are hydrocarbon metabolites that play key roles in plants for light sensing, cell signaling, and oxidative protection but have undefined roles in P. falciparum. Furthermore, human cells do not depend on carotenoid biosynthesis and thus are not affected by inhibitors of this pathway. The proposed studies will use innovative biochemical and genetic approaches to identify the first two enzymes in the parasite carotenoid biosynthesis pathway and to tag these genes to encode a recently developed regulation system that enables protein expression to be selectively turned off. The expected outcome of this proposal is to rigorously evaluate if these P. falciparum enzymes required for carotenoid biosynthesis are essential for blood-stage parasite viability and can thereby serve as new parasite-specific antimalarial drug targets. Success in the proposed project will provide a basis for future drug development efforts to specifically target these essential enzymes. These new therapies would have novel mechanisms of action orthogonal to and thus suitable for partnering with currently used drugs. These studies will also unravel new parasite biology by identifying a novel metabolic pathway and providing a framework for future work to define the critical cellular functions of carotenoids during blood and liver-stage infection by Plasmodium parasites. Finally, insights and treatments resulting from the proposed studies are likely to be applicable to treat other human parasites, including Toxoplasma gondii and Babesia, that also depend on carotenoid biosynthesis.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810060
Entities
People
- Paul Sigala
Organizations
- United States Army
- University of Utah