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Conference Agenda

Overview and details of the sessions of this conference. Please select a date or location to show only sessions at that day or location. Please select a single session for detailed view (with abstracts and downloads if available).

Daily Overview

Session

CP15.1: Drugs & Drug Resistance 2 - 5 min talks sponsored by Institute for Biomedicine and Glycomics, Griffith University
Location: Lecture Theatre 1
Session Chair: Jacinta Macdonald, Griffith University
Session Chair: Rohith Kutty, Griffith University

Presentation 3

Investigating putative target/s of the malaria drug proguanil identified using solvent-induced protein precipitation

Rohith Kutty¹, Wisam Dawood¹, Gillian Fisher¹, Jacinta Macdonald¹, Patrick Tumwebaze¹, Yijia Ji³, Joshua Morrow³, Andrew Riches², John Ryan², Ghizal Siddiqui³, Darren Creek³, Tina Skinner-Adams¹, Katherine Andrews¹

1: Institute for Biomedicine and Glycomics, Griffith University, Nathan, Queensland, Australia; 2: Commonwealth Scientific and Industrial Research Organization, Biomedical Manufacturing, Clayton, Victoria, Australia; 3: Monash Institute of Pharmaceutical Sciences, Monash University, Victoria, Australia

Malaria remains a persistent global health threat leading to around 600,000 deaths annually. Resistance of Plasmodium parasites to most available drugs is significantly impacting prevention and control efforts. Combating resistance requires a clear understanding of drug mode of action, which remains incomplete for several current options. One such drug combination is atovaquone-proguanil. Atovaquone targets the cytochrome bc1 complex, and proguanil, originally developed as a prodrug, is converted in vivo to the dihydrofolate reductase (DHFR) inhibitor cycloguanil. While proguanil has been shown to potentiate the activity of atovaquone in vitro, for decades proguanil was thought to lack intrinsic activity. However, we showed that proguanil has a potent slow-acting in vitro antiplasmodial activity that is distinct from the folate metabolism pathway1. To try to identify the target/s of proguanil’s slow-action activity, we employed solvent-induced protein precipitation combined with mass spectrometry to assess protein stability in the presence of proguanil. Here, data will be presented on one of several candidate proteins stabilized by proguanil. Conditional knockdown is being performed in wildtype Plasmodium falciparum using TetR-DOZI and CRISPR-Cas9 Guide RNA constructs. Future work will include confirmation of knockdown and phenotypic assays with proguanil to assess changes in sensitivity to this drug.