JavaScript is Disabled
Your browser's JavaScript functionality is disabled. It has to be enabled to use this function of ConfTool.
Here you can find information on how to enable JavaScript
If you have any problems, please contact the organizers at parasitologycommunicator@gmail.com.

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

S1: Nick White Memorial Symposium
Location: Lecture Theatre 1
Session Chair: Katherine Andrews, Griffith University
Session Chair: Colin Sutherland, LSHTM

Presentation 2

Investigating resistance to the malaria drug proguanil

Katherine Andrews¹, Patrick Tumwebaze¹, Gillian M. Fisher¹, Yunan Qian¹, Wisam Dawood¹, Jacinta Macdonald¹, David A. Fidock², Oriana Kreutzfeld³, Philip Rosenthal³, Andrew G. Riches⁴, John H. Ryan⁴, Tina S. Skinner-Adams¹

1: Institute for Biomedicine and Glycomics, Griffith University, Nathan, Queensland, Australia; 2: Department of Microbiology and Immunology, Columbia University Irving Medical Center, New York, USA; 3: Department of Medicine, University of California San Francisco, California, USA; 4: Commonwealth Scientific and Industrial Research Organization, Biomedical Manufacturing, Clayton, Victoria, Australia

The combination of atovaquone and proguanil (e.g., Malarone^®) has been used for decades for malaria prevention and treatment. Atovaquone inhibits cytochrome bc₁ (complex III), a component of the Plasmodium mitochondrial electron transport chain (mETC). Proguanil is a biguanide prodrug that is metabolized in vivo by liver cytochrome P450 (CYP2C19) enzymes into cycloguanil, a dihydrofolate reductase (DHFR) inhibitor that blocks the synthesis of pyrimidines which are required for nucleic acid synthesis. Proguanil can potentiate the activity of atovaquone in vitro, and we demonstrated that this drug also has slow action in vitro activity against P. falciparum (e.g., Pf3D7 96h IC₅₀ 0.1 µM) that is independent of DHFR inhibition and isoprenoid metabolism and does not appear to be directly linked to pyrimidine synthesis. However, our understanding of the clinical implications of proguanil’s intrinsic activity are complicated by an incomplete understanding of the slow action mechanism of this drug and the lack of information on clinical resistance to proguanil. To address this, we have utilised a range of approaches to investigate resistance mechanisms associated with proguanil, including generation of proguanil-resistant P. falciparum lines and examining differences in sensitivity to proguanil by P. falciparum lab lines, field isolates and the zoonotic P. cynomolgi species. These data will be discussed in the context of clinical use of proguanil in the atovaquone and proguanil combination.