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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

CP8: Drugs & Drug Resistance 1 - 10 min talks
Location: Lecture Theatre 1
Session Chair: Christopher Hart, Griffith University
Session Chair: Hannah Smith, Griffith University

Presentation 3

Identifying the mechanism of action of the antiplasmodial pantothenate analogue AH-2-45 in Plasmodium falciparum

Scarlett Cox¹, Zaynab Radih¹, Chunling Blue Lan², Karine Auclair², Kevin J. Saliba¹

1: Australian National University, Australia; 2: McGill University, Canada

Plasmodium falciparum, the deadliest human malaria parasite, has developed resistance to all clinically used antimalarials, highlighting the need for new compounds with novel modes of action. Pantothenate analogues kill P. falciparum by targeting the biosynthesis or utilisation of coenzyme A (CoA), an essential enzyme cofactor. Pantothenamides (PanAms), pantothenate analogues in which the carboxyl group is replaced by an amide group, exhibit potent in vitro activity. Unfortunately, PanAms are degraded in vivo by human pantetheinase. Modification of the labile amide bond has given rise to pantetheinase-resistant PanAm mimics. AH-2-45, a ring-substituted PanAm mimic, exhibits nanomolar antiplasmodial activity and is metabolised by CoA biosynthesis enzymes into a CoA antimetabolite, proposed to inhibit downstream CoA-dependent pathways. However, its precise target remains unknown. Whole-genome sequencing of in vitro-generated AH-2-45-resistant P. falciparum revealed a missense mutation in the gene encoding the endoplasmic reticulum-resident glycerol-3-phosphate 1-O-acyltransferase (PfGPAT), an essential CoA-dependent enzyme involved in phospholipid biosynthesis. We are currently genetically validating PfGPAT as the AH-2-45 resistance determinant and characterising the functional impact of the resistance-associated mutation using PfGPAT activity assays. Elucidating this mechanism may establish PfGPAT as a novel antimalarial drug target and guide structural optimisations of the AH-2-45 antimetabolite and related PanAm mimics.