Discovering resistance-resistant antimalarial drug target

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PROJECT SUMMARY/ABSTRACT Malaria continues to be a major burden on global health, infecting over 220 million and killing over 400 thousand people annually. Although the past fifteen years of enhanced international efforts to eradicate malaria has reduced malaria incidence worldwide, this progress has stagnated in recent years. Antimalarial drugs are foundational in reducing disease and transmission, but resistance has developed within twelve years of clinical introduction to every antimalarial drug developed since 1945 including the current front-line artemisinin-based combination therapies. This ease with which parasites develop resistance clearly indicates that innovative approaches to antimalarial drug discovery are urgently needed. Here we propose two separate strategies designed to discover antimalarial drug targets for which resistance will be difficult to develop in the field. The first approach will characterize metabolic adaptations acquired by malaria parasites upon becoming resistant to a primary drug, with a focus on identifying novel metabolic dependencies (vulnerabilities) of resistant parasites. We propose to employ our extensive experience in metabolomic characterization of the malaria parasite, Plasmodium falciparum, to compare drug-sensitive and drug-resistant parasite biochemical architectures. Metabolomics will be used to elucidate altered metabolic pathways in resistant parasites in order to reveal collateral sensitivities that we will validate as putative drug targets using either small molecule pathway inhibitors or genetic knockdowns of relevant target enzymes. The ultimate goal will be to target these collateral sensitivities together with the primary drug to lock the parasite into a drug-sensitive state, as the adaptations required for primary resistance are no longer available, thus providing an enduring, complementary combination therapy. For the second strategy, we propose to discover host metabolic processes that are critical to support blood-stage development of P. falciparum. The blood stages of the malaria parasite life cycle are responsible for both the symptomology and the human-to- mosquito transmission of the parasite, and critically rely on nutrients from human serum. However, we have found that different human serum lots are highly variable in their ability to support parasite growth and transmission. To identify serum metabolites that correlate with parasite phenotypic readouts, we propose to utilize our metabolomic approaches in combination with standard parasite growth and transmission assays. Using serum lots from healthy donors, this approach will identify naturally variable, and thus potentially targetable, host processes upon which the parasite is reliant. Targeting host factors takes the evolutionary control away from the parasite, reducing the probability of resistance emergence. In all, this proposal seeks to address the persistent problem of antimalarial drug resistance development by evaluating two new strategies for discovering resistance-resistant drug targets.