Effective drug combination for Caenorhabditis elegans nematodes discovered by output-driven feedback system control technique.
Effective drug combination for Caenorhabditis elegans nematodes discovered by output-driven feedback system control technique.
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DOI：
10.1126/sciadv.aao1254
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发表时间：
2017-10
期刊：
影响因子：
13.6
通讯作者：
Pandey S
中科院分区：
文献类型：
--
作者：
Ding X;Njus Z;Kong T;Su W;Ho CM;Pandey S
一种工程方法产生了四种抗线虫药物的高效组合，其剂量比单个药物低。来自寄生线虫（或蛔虫）的感染对人类和牲畜造成了重大的疾病负担和生产力损失。目前可用于治疗这些感染的有限数量的驱虫药（或抗寄生虫药物）正在迅速失去效力，因为寄生虫的多药耐药性已成为一项全球卫生挑战。我们提出了一种工程方法来发现一种驱虫药物组合，它比四种单独的药物更有效地杀死野生型秀丽隐杆线虫。在实验中，将自由游动的单个蠕虫封闭在微流体药物环境中，以评估蠕虫运动的质心速度和轨迹曲率。在分析每次迭代的行为数据后，采用反馈系统控制（FSC）方案预测新药组合进行试验。通过微分进化搜索，获得了产生最小质心速度和高轨迹曲率的获胜药物组合，同时要求每种药物的浓度低于其EC50浓度。FSC方法是无模型的，不需要任何关于药物药理学、信号通路或动物生物学的信息。为了对抗多药耐药，本文提出的方法适用于在秀丽隐杆线虫、寄生线虫和其他小型模式生物上发现新的有效的驱虫剂组合。
An engineering approach yields a highly potent combination of four antinematode drugs at lower dosages than individual drugs. Infections from parasitic nematodes (or roundworms) contribute to a significant disease burden and productivity losses for humans and livestock. The limited number of anthelmintics (or antinematode drugs) available today to treat these infections are rapidly losing their efficacy as multidrug resistance in parasites becomes a global health challenge. We propose an engineering approach to discover an anthelmintic drug combination that is more potent at killing wild-type Caenorhabditis elegans worms than four individual drugs. In the experiment, freely swimming single worms are enclosed in microfluidic drug environments to assess the centroid velocity and track curvature of worm movements. After analyzing the behavioral data in every iteration, the feedback system control (FSC) scheme is used to predict new drug combinations to test. Through a differential evolutionary search, the winning drug combination is reached that produces minimal centroid velocity and high track curvature, while requiring each drug in less than their EC50 concentrations. The FSC approach is model-less and does not need any information on the drug pharmacology, signaling pathways, or animal biology. Toward combating multidrug resistance, the method presented here is applicable to the discovery of new potent combinations of available anthelmintics on C. elegans, parasitic nematodes, and other small model organisms.
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