Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States.
ACS Infect Dis. 2021 Jul 9;7(7):1923-1931. doi: 10.1021/acsinfecdis.0c00900. Epub 2021 May 10.
Artemisinin-based combination therapies (ACTs), the World Health Organization-recommended first-line therapy for uncomplicated falciparum malaria, has led to significant decreases in malaria-associated morbidity and mortality in the past two decades. Decreased therapeutic efficacy of artemisinins, the cornerstone of ACTs, is threatening the gains made against this disease. As such, novel therapeutics with uncompromised mechanisms of action are needed to combat parasite-mediated antimalarial resistance. We have previously reported the antimalarial activity of -specific proteasome inhibitors in conjunction with a variety of antimalarials in clinical use or in preclinical investigations and of proteasome mutants generated in response to these inhibitors. Here, we discover that despite harboring K13, which has conventionally mediated artemisinin resistance in vitro as measured by increased survival in ring-stage survival assays (RSA), the Cam3.II strain parasites of Cambodian origin that have acquired an additional mutation in the proteasome display increased susceptibility to DHA and OZ439. This discovery implicates the proteasome in peroxide susceptibilities and has favorable implications on the use of peroxide and proteasome inhibitor combination therapy for the treatment of artemisinin-resistant malaria.
青蒿素为基础的联合疗法（ACTs）是世界卫生组织推荐的治疗无并发症恶性疟原虫疟疾的一线疗法，在过去二十年中，它显著降低了疟疾相关的发病率和死亡率。青蒿素作为 ACTs 的基石，其治疗效果下降，威胁到对抗这种疾病所取得的成果。因此，需要具有不受影响作用机制的新型疗法来对抗寄生虫介导的抗疟药物耐药性。我们之前曾报道过 - 特异性蛋白酶体抑制剂与各种临床使用或临床前研究中的抗疟药物联合使用的抗疟活性，以及针对这些抑制剂产生的蛋白酶体突变体。在这里，我们发现尽管含有 K13，其在体外通过环体存活测定（RSA）中增加的存活率来传统地介导青蒿素耐药性，但柬埔寨来源的 Cam3.II 株寄生虫在蛋白酶体中获得了额外的突变，对 DHA 和 OZ439 的敏感性增加。这一发现将蛋白酶体与过氧化物敏感性联系起来，并对使用过氧化物和蛋白酶体抑制剂联合治疗治疗青蒿素耐药性疟疾具有有利影响。
