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An Interdisciplinary Research Centre at the University of Cambridge
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Wed 20 Mar 14:00: Cutting back malaria: CRISPR-based approaches for antimalarial target discovery

Mon, 11/03/2024 - 14:10
Cutting back malaria: CRISPR-based approaches for antimalarial target discovery

The repeated emergence of antimalarial resistance underscores the importance of identifying new drug targets, as well as understanding the genetic architecture of current resistance pathways and any associated fitness costs. We have developed several genomics-based approaches that leverage CRISPR editing of the Plasmodium falciparum genome to validate causal resistance mutations and explore the essentiality and biological function of gene families as antimalarial targets. To more efficiently determine if compounds kill the parasite via known modes-of-action, we have generated a panel of barcoded parasite lines that encompass a wide spectrum of the known Plasmodium resistome, and have miniaturised a compound-screening assay to allow semi-automated liquid handling of parasite cultures. Competitive growth of drug-resistant lines also reveals the fitness cost of resistance. To overcome a bottleneck in evolution of resistance in the lab, we have also developed “mutator” parasite lines with an elevated mutation rate to increase the genetic complexity of parasite cultures. Finally, we are exploring whether non-coding mutations, specifically in lncRNAs, might also contribute to the parasite resistome. Collectively these approaches aim to accelerate the identification and validation of potential new targets, as well as understand the breadth of the parasite response to antimalarial challenge.

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Thu 18 Apr 14:00: E. coli and the Game of Clones Host – Kate Baker

Wed, 28/02/2024 - 11:21
E. coli and the Game of Clones

Escherichia coli is the most studied microbe to date and its genomic and phenotypic evolution has been mapped to a great detail over several decades. However, significant knowledge gaps remain to explain the stable equilibria of clone population frequencies and transient population changes discovered using representative high-resolution genomic surveys. Here we review recent results based on in-depth analysis of the E. coli plasmidome and its importance for understanding the Game of Clones.

Host – Kate Baker

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