Molecular Parasitology, Institute of Tropical Medicine, Antwerp, Belgium.
Advanced Database Reasearch and Modelling (ADReM), Department of Mathematics and Computer Science, University of Antwerp, Antwerp, Belgium.
mSphere. 2018 Apr 18;3(2). doi: 10.1128/mSphere.00548-17. Print 2018 Apr 25.
Antimonials (Sb) were used for decades for chemotherapy of visceral leishmaniasis (VL). Now abandoned in the Indian subcontinent (ISC) because of resistance, this drug offers a unique model for understanding drug resistance dynamics. In a previous phylogenomic study, we found two distinct populations of : the core group (CG) in the Gangetic plains and ISC1 in the Nepalese highlands. Sb resistance was only encountered within the CG, and a series of potential markers were identified. Here, we analyzed the development of resistance to trivalent antimonials (Sb) upon experimental selection in ISC1 and CG strains. We observed that (i) baseline Sb susceptibility of parasites was higher in ISC1 than in the CG, (ii) time to Sb resistance was higher for ISC1 parasites than for CG strains, and (iii) untargeted genomic and metabolomic analyses revealed molecular changes along the selection process: these were more numerous in ISC1 than in the CG. Altogether these observations led to the hypothesis that CG parasites are preadapted to Sb resistance. This hypothesis was experimentally confirmed by showing that only wild-type CG strains could survive a direct exposure to the maximal concentration of Sb The main driver of this preadaptation was shown to be , a gene involved in Sb sequestration and amplified in an intrachromosomal amplicon in all CG strains characterized so far. This amplicon emerged around 1850 in the CG, well before the implementation of antimonials for VL chemotherapy, and we discuss here several hypotheses of selective pressure that could have accompanied its emergence. The "antibiotic resistance crisis" is a major challenge for scientists and medical professionals. This steady rise in drug-resistant pathogens also extends to parasitic diseases, with antimony being the first anti- drug that fell in the Indian subcontinent (ISC). Leishmaniasis is a major but neglected infectious disease with limited therapeutic options. Therefore, understanding how parasites became resistant to antimonials is of commanding importance. In this study, we experimentally characterized the dynamics of this resistance acquisition and show for the first time that some populations of the ISC were preadapted to antimony resistance, likely driven by environmental factors or by drugs used in the 19th century.
抗梅毒剂（Sb）曾被用于治疗内脏利什曼病（VL）数十年。由于耐药性，这种药物现在在印度次大陆（ISC）被弃用，但它为我们理解耐药性动态提供了一个独特的模型。在之前的系统基因组学研究中，我们发现了两种不同的 种群：恒河平原的核心群（CG）和尼泊尔高原的 ISC1。只有在 CG 中才会遇到 Sb 耐药性，并且确定了一系列潜在的标记。在这里，我们分析了在 ISC1 和 CG 菌株中通过实验选择对三价 Sb 产生耐药性的发展情况。我们观察到：（i）ISC1 中的寄生虫对 Sb 的基础敏感性高于 CG，（ii）ISC1 寄生虫产生 Sb 耐药性的时间比 CG 菌株长，以及（iii）非靶向基因组和代谢组学分析显示，随着选择过程的进行，分子发生了变化：ISC1 中的变化比 CG 中更多。所有这些观察结果都表明 CG 寄生虫预先适应了 Sb 耐药性。通过表明只有野生型 CG 菌株才能在直接暴露于 Sb 的最大浓度下存活，这一假设得到了实验验证。这种预适应的主要驱动因素是 ，这是一个参与 Sb 螯合的基因，在迄今为止表征的所有 CG 菌株的染色体内扩增子中都被扩增。这个扩增子大约在 1850 年出现在 CG 中，远早于 Sb 用于 VL 化疗的时间，我们在这里讨论了几种可能伴随其出现的选择压力假说。“抗生素耐药性危机”是科学家和医疗专业人员面临的主要挑战。这种耐药性病原体的稳定上升也扩展到了寄生虫病，而 Sb 是第一种在印度次大陆（ISC）失效的抗寄生虫药物。利什曼病是一种主要但被忽视的传染病，治疗选择有限。因此，了解寄生虫对 Sb 产生耐药性的机制非常重要。在这项研究中，我们通过实验对这种耐药性获得的动力学进行了表征，并首次表明，ISC 的一些 种群预先适应了 Sb 耐药性，这可能是由环境因素或 19 世纪使用的药物驱动的。
