The enemy within: Targeting host–parasite interaction for antileishmanial drug discovery

The state of antileishmanial chemotherapy is strongly compromised by the emergence of drug-resistant Leishmania. The evolution of drug-resistant phenotypes has been linked to the parasites’ intrinsic genome instability, with frequent gene and chromosome amplifications causing fitness gains that are directly selected by environmental factors, including the presence of antileishmanial drugs. Thus, even though the unique eukaryotic biology of Leishmania and its dependence on parasite-specific virulence factors provide valid opportunities for chemotherapeutical intervention, all strategies that target the parasite in a direct fashion are likely prone to select for resistance. Here, we review the current state of antileishmanial chemotherapy and discuss the limitations of ongoing drug discovery efforts. We finally propose new strategies that target Leishmania viability indirectly via mechanisms of host–parasite interaction, including parasite-released ectokinases and host epigenetic regulation, which modulate host cell signaling and transcriptional regulation, respectively, to establish permissive conditions for intracellular Leishmania survival.

利什曼原虫（Leishmania）耐药株的出现，严重损害了抗利什曼虫化疗的当前发展态势。耐药表型的演化与该寄生虫固有的基因组不稳定性密切相关：频繁发生的基因与染色体扩增可带来适合度增益，而这类增益会被包括抗利什曼虫药物存在在内的环境因素直接筛选。尽管利什曼原虫独特的真核生物学特性，以及其对寄生虫特异性毒力因子的依赖，为化疗干预提供了切实可行的契机，但所有直接靶向该寄生虫的策略，都极有可能诱导耐药性的筛选。本文综述了当前抗利什曼虫化疗的发展现状，并探讨了正在进行的药物研发工作所存在的局限性。最后，本文提出了通过宿主-寄生虫互作机制间接靶向利什曼原虫生存能力的新策略，其中包括寄生虫分泌的胞外激酶（ectokinases）以及宿主表观遗传调控：二者可分别调控宿主细胞信号通路与转录调控过程，从而为细胞内利什曼原虫的存活建立许可性微环境。