Understanding the Development of Compensatory Pathways in a Mutant Malaria Parasite Harbouring Hypomorphic Allele of Plant-Like Kinases

Drug resistance is a major challenge in combating malaria. Our study aims to identify compensatory pathways in malaria parasites containing hypomorphic allele of essential protein kinases. Targeting two kinases simultaneously may be a better strategy that avoids developing drug resistance against individual kinases.

Gene editing using CRISPR-Cas9 has profoundly benefited malaria research and has been instrumental performing allelic exchanges, endogenous tagging, conditional knockout, and knockdown of target gene. The molecular mechanism of drug resistance, understanding target gene function and study of host parasite interaction can now be studied with greater ease. The current experimental challenges include heterologous protein expression in E.coli due to the high richness of the plasmodium genome.

Additionally, of target effect of CRISPR-Cas9 complicated data interpretation and led to erroneous results. Low transcription efficiency with the malaria parasite increases the time required for generating the desired genetic modification. Our findings suggests that targeting a single kinase in the malaria parasite may lead to compensatory over expression of other kinases.

This raises new question about the potential for adaptive resistance and whether dual kinase inhibition could effectively prevent such adaptation, opening avenues for the combination therapeutic strategies. In the future, our laboratory will target other essential protein kinases of malaria parasites using chemical genetics. Transcriptional rewiring in the mutant parasites will help in identifying compensatory pathways that may be simultaneously targeted to prevent development of drug resistance against individual kinases.