Department of Microbiology and Immunology, Weill Cornell Medical College, New York, New York, USA.
Department of Internal Medicine, Division of Infectious Diseases, Weill Cornell Medical College, New York, New York, USA.
Antimicrob Agents Chemother. 2020 May 21;64(6). doi: 10.1128/AAC.02021-19.
Malaria parasites invade and replicate within red blood cells (RBCs), extensively modifying their structure and gaining access to the extracellular environment by placing the plasmodial surface anion channel (PSAC) into the RBC membrane. Expression of members of the cytoadherence linked antigen gene 3 () family is required for PSAC activity, a process that is regulated epigenetically. PSAC is a well-established route of uptake for large, hydrophilic antimalarial compounds, and parasites can acquire resistance by silencing gene expression, thereby reducing drug uptake. We found that exposure to sub-IC concentrations of the histone methyltransferase inhibitor chaetocin caused substantial changes in both gene expression and RBC permeability, and reversed acquired resistance to the antimalarial compound blasticidin S that is transported through PSACs. Chaetocin treatment also altered progression of parasites through their replicative cycle, presumably by changing their ability to modify chromatin appropriately to enable DNA replication. These results indicate that targeting histone modifiers could represent a novel tool for reversing epigenetically acquired drug resistance in .
疟原虫在红细胞（RBC）内入侵和复制，通过将疟原虫表面阴离子通道（PSAC）置于 RBC 膜中，广泛改变其结构并获得细胞外环境的通路。PSAC 活性需要细胞黏附相关抗原基因 3（）家族成员的表达，这是一个受表观遗传调控的过程。PSAC 是大型亲水性抗疟化合物摄取的既定途径，寄生虫可以通过沉默基因表达来获得耐药性，从而减少药物摄取。我们发现，暴露于低于 IC 浓度的组蛋白甲基转移酶抑制剂 chaetocin 会导致基因表达和 RBC 通透性的显著变化，并逆转了通过 PSAC 转运的抗疟化合物 blasticidin S 的获得性耐药。chaetocin 处理还改变了寄生虫在其复制周期中的进展，推测是通过改变它们适当修饰染色质的能力来实现 DNA 复制。这些结果表明，靶向组蛋白修饰剂可能代表一种逆转获得性药物耐药性的新工具。
