Malaria parasites rely on a tiny protein machine inside their cells—complex III—to generate energy, and this project will map exactly how that machine differs from the human version. The parasite that causes malaria infects hundreds of millions of people each year, and resistance to the current frontline drug, artemisinin, has already emerged globally. Existing drugs that target complex III, such as atovaquone, work well initially but parasites can become resistant to them rapidly. Researchers do not yet know the precise details of how the parasite’s complex III is built or why certain inhibitors bind to it but not to the human counterpart. This project will use advanced structural methods to reveal the composition and mechanism of the malaria complex III, focusing on the parts that are unique to the parasite. It will also map exactly how at least two different inhibitors bind to two separate pockets on the complex. If successful, this fundamental understanding could directly inform the development of new antimalarial drugs that are effective against drug-resistant parasites, potentially saving hundreds of thousands of lives each year.
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The parasite that causes malaria infects hundreds of millions of people and causes hundreds of thousands of deaths every year, primarily in children under the age of five in Africa. Global malaria control is heavily dependent on antimalarial drugs, but resistance to the current frontline antimalarial, artemisinin, has emerged globally, threatening current control efforts. New drugs and new drug targets are urgently needed. Almost all complex cells, including the cells in our body and the single-celled parasites that cause malaria, require an energy-converting compartment called the mitochondrion to survive. Inside this mitochondrion there is a chain of protein complexes or "micro-machines" that drive the conversion of energy. These micro-machines are essential for the malaria parasite's ability to grow inside human red blood cells, which causes the symptoms of malaria, and for their ability to spread from person to person via mosquitoes. Due to these critical roles, inhibitors that disrupt the activity of these parasite micro-machines, without affecting their human counterparts, can make effective anti-parasitic drugs. There is already one antimalarial drug, atovaquone, along with a series of inhibitors in different stages of drug development, which target complex III (CIII), the third micro-machine in the chain, but we currently do not know the exact details of how this complex works. Likewise, we cannot explain why these inhibitors interacts so well with parasite CIII, and not the human counterpart. The answers to both questions, which our project aims to provide, will likely help make better drugs. Human CIII is made of eleven parts, eight of which supports its stability and its interactions with the other micro-machines in the chain. We and others found that parasite CIII is lacking some of these eight parts, and instead contains parts not found in the human complex. These differences in malaria and human CIII composition are intriguing as they represent divergence in a fundamental cell biology process and a unique feature of this deadly infectious organism which could potentially be targeted by new drugs. It is not currently known how this divergent composition affects CIII structure and function. This project will reveal how these unique parts of parasite CIII function in parasite growth and survival, and further examine their importance for the interaction between micro-machines in the chain, and their role in parasite development into their transmissible form. While atovaquone is highly potent, the malaria parasite can become resistant to it rapidly, so other inhibitors that target the parasite CIII and are active against atovaquone resistant parasites need to be developed. CIII has two pockets where drugs could bind: atovaquone binds one pocket, while some of the newly developed inhibitors bind to the other. We will use advanced structural approaches to precisely map the binding interaction of at least two inhibitors, which each bind a different pocket. This will provide critical information to support the future development of new antimalarial drugs. In summary, this project will uncover the composition, function, and mechanism of the malaria CIII focusing on the features that are divergent from the human complex. It will therefore expand our understanding of a fundamental cell biology process in divergent organisms, while also providing detailed insight into how drugs are able to inhibit malaria CIII and informing antimalarial drug development.
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