Grant: Discovery Grants Program - Individual

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.