Characterization and role of the Drug / Metabolite Transporter (DMT) superfamily in drug resistance using a bodonid kinetoplastid model

对寄生虫病的研究创造了许多机会和挑战，因为所有人和牲畜的寄生虫感染都是通过药物的使用来控制的。这些药物已经连续使用了60多年，因此产生了抗药性或耐受性。由于疫苗不是(目前)许多此类感染的可行选择，药物是控制计划的中流砥柱。对于大多数寄生虫病来说，迫切需要开发新的更好的药物，但要做到这一点，就需要更好地了解耐药性，试图绕过或克服它，而且有必要寻找寄生虫的新的特定细胞靶点。该研究计划的长期目标是了解寄生虫耐药的机制(S)。为了实现这一目标，在接下来的五年里，将开发盐生梭子虫模型，以研究对小米那烯、异二甲双胺、五甲胺和二氟甲基鸟氨酸的耐药性，这四种药物通常用于治疗动体原生动物引起的感染。该计划将专注于药物/代谢物转运体(DMT)超家族，并将涉及单药和多药耐药菌株的基因组和RNA测序。通过比较药物敏感和耐药菌株中一组有针对性的耐药相关基因，将有可能量化与特定目标相关的基因变化。通过比较单药耐药株对多药耐药株随时间的发展，可以确定获得耐药性的速度有多快。从长远来看，确定这些靶点可能是开发未来药物或对目前使用的药物提出修改建议的第一步。这项NSERC发现基金中提出的研究将支持教育培训和发展，从而培养出接受过分子生物学和功能基因组学培训的高素质人才。药物靶点的确定可能有助于设计新的化合物，对于那些已经产生抗药性的化合物，或者有助于识别具有类似作用机制的已知类别的具有潜在治疗价值的化合物。要了解耐药性，了解寄生虫基因组和蛋白质组是必不可少的。

Study of parasitic diseases creates a number of opportunities and challenges as all parasitic infections in humans and livestock are controlled by the use of drugs. These drugs have been in continuous use, in some cases for over 60 years, and as such a resistance or tolerance has developed. Since vaccines are not a viable option (at present) for many of these infections, drugs are the mainstay of control programs. For most parasitic diseases, there is an urgent need to develop new and better drugs but to do this an improved understanding of drug resistance, to try to circumvent or overcome it, and the search for new specific cellular targets of parasites are warranted. The long term objective of the research program is to understand the mechanism(s) of drug resistance in parasitic organisms. Towards realizing that goal, over the next five years the C. salmositica model will be developed to study resistance to diminazene, isometamidium, pentamdine and difluoromethylornithine, four drugs commonly used to treat infections caused by kinetoplastid protozoans. The program will focus on the drug/metabolite transporter (DMT) superfamily and will involve genome and RNA sequencing of single agent and multidrug resistant strains. By comparing a targeted set of resistance-associated genes in drug sensitive and resistant strains, it will be possible to quantify the genetic changes associated with a specific target. A comparison of the development of resistance in single-agent resistant strains to MDR strains over time will allow identification of how rapidly resistance is acquired. In the long term, identification of these targets may be the first step towards the development of future drugs or for suggesting modifications to currently used drugs. The research proposed in this NSERC Discovery Grant will support educational training and development, resulting in highly qualified personnel with training in molecular biology and functional genomics . The identification of drug targets could help in the design of new compounds, for those in which resistance has developed, or in the identification of known classes of compounds with a similar mechanism of action that have potential therapeutic value. To understand drug resistance, an understanding of parasite genomes and proteomes is essential.