Department of Entomology, Plant Pathology and Nematology, University of Idaho, Moscow, ID 83843, USA.
Department of Entomology, University of Arizona, Tucson, AZ 85721, USA.
Biomolecules. 2021 May 29;11(6):807. doi: 10.3390/biom11060807.
Malaria parasites require pantothenate from both human and mosquito hosts to synthesize coenzyme A (CoA). Specifically, mosquito-stage parasites cannot synthesize pantothenate de novo or take up preformed CoA from the mosquito host, making it essential for the parasite to obtain pantothenate from mosquito stores. This makes pantothenate utilization an attractive target for controlling sexual stage malaria parasites in the mosquito. CoA is synthesized from pantothenate in a multi-step pathway initiated by the enzyme pantothenate kinase (PanK). In this work, we manipulated PanK activity and assessed the impact of mosquito PanK activity on the development of two malaria parasite species with distinct genetics and life cycles: the human parasite and the mouse parasite 17XNL. We identified two putative PanK isoforms encoded by a single gene and expressed in the mosquito midgut. Using both RNAi and small molecules with reported activity against human PanK, we confirmed that PanK manipulation was associated with corresponding changes in midgut CoA levels. Based on these findings, we used two small molecule modulators of human PanK activity (PZ-2891, compound 7) at reported and ten-fold EC doses to examine the effects of manipulating PanK on malaria parasite infection success. Our data showed that oral provisioning of 1.3 nM and 13 nM PZ-2891 increased midgut CoA levels and significantly decreased infection success for both species. In contrast, oral provisioning of 62 nM and 620 nM compound 7 decreased CoA levels and significantly increased infection success for both species. This work establishes the CoA biosynthesis pathway as a potential target for broadly blocking malaria parasite development in anopheline hosts. We envision this strategy, with small molecule PanK modulators delivered to mosquitoes via attractive bait stations, working in concert with deployment of parasite-directed novel pantothenamide drugs to block parasite infection in the human host. In mosquitoes, depletion of pantothenate through manipulation to increase CoA biosynthesis is expected to negatively impact survival by starving the parasite of this essential nutrient. This has the potential to kill both wild type parasites and pantothenamide-resistant parasites that could develop under pantothenamide drug pressure if these compounds are used as future therapeutics for human malaria.
疟原虫需要从人类和蚊子宿主中获取泛酸来合成辅酶 A (CoA)。具体来说，蚊子阶段的寄生虫不能从头合成泛酸，也不能从蚊子宿主中摄取已形成的 CoA，因此寄生虫必须从蚊子的储存中获取泛酸。这使得泛酸的利用成为控制蚊子中性阶段疟原虫的一个有吸引力的目标。CoA 是由酶泛酸激酶 (PanK) 启动的多步途径从泛酸合成的。在这项工作中，我们操纵 PanK 活性，并评估蚊子 PanK 活性对两种具有不同遗传和生命周期的疟原虫物种发育的影响：人类寄生虫 和老鼠寄生虫 17XNL。我们鉴定了由单个基因编码并在蚊子中肠表达的两种推定的 PanK 同工酶。使用 RNAi 和据报道对人 PanK 具有活性的小分子，我们证实 PanK 的操作与中肠 CoA 水平的相应变化有关。基于这些发现，我们使用两种人 PanK 活性的小分子调节剂（PZ-2891，化合物 7）在报道的和十倍 EC 剂量下，检查操纵 PanK 对疟原虫感染成功的影响。我们的数据表明，口服给予 1.3 nM 和 13 nM 的 PZ-2891 增加了中肠 CoA 水平，并显著降低了两种 物种的感染成功率。相比之下，口服给予 62 nM 和 620 nM 的化合物 7 降低了 CoA 水平，并显著增加了两种 物种的感染成功率。这项工作确立了 CoA 生物合成途径作为一种潜在的靶点，可在按蚊宿主中广泛阻断疟原虫的发育。我们设想，通过有吸引力的诱饵站向蚊子提供小分子 PanK 调节剂，并与部署针对新型泛氨酰胺药物以阻断人类宿主中的寄生虫感染协同作用，从而阻断寄生虫感染。在蚊子中，通过操纵增加 CoA 生物合成来耗尽泛酸，预计会通过使寄生虫缺乏这种必需营养素而使寄生虫饿死，从而对 生存产生负面影响。如果这些化合物被用作人类疟疾的未来治疗方法，那么这有可能杀死野生型寄生虫和泛氨酰胺耐药寄生虫，这些寄生虫在泛氨酰胺药物压力下可能会产生。
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