Investigation of cyclization-blocked proguanil analogues for malaria
We have made the exciting discovery that the clinically used antimalarial drug proguanil has much more potent activity than previously thought. Proguanil has been used for decades in combination with the cytochrome bc1 inhibitor atovaquone (as Malarone®). The activity of proguanil has up until now been thought to be due to its in vivo cyclization metabolite cycloguanil, a DHFR inhibitor, and by potentiating atovaquone activity. In this project, cyclization blocked analogues of proguanil will be investigated as potential new combination partners for atovaquone. Approaches will include in vitro growth inhibition assays, combination studies, time of kill assay and in vivo efficacy testing in murine models of malaria.
Primary supervisor: Professor Katherine Andrews
Other supervisor: A/Prof Tina Skinner-Adams, Dr Gillian Fisher
To apply: Contact Prof Katherine Andrews with your CV at k.andrews@griffith.edu.au
Investigation of HDAC inhibitors as antimalarial drug leads
Histone deacetylase (HDAC) enzymes play key roles in regulating important cellular processes and are potential new drug targets for malaria. We have developed unique assays for HDAC inhibitor drug discovery, including an in silico quantitative structure activity relationship (QSAR) model and hyperacetylation ELISA. This project will focus on in vitro and in vivo testing of new HDAC inhibitors and in vitro mode of action studies including evolution of resistant parasites combined with whole genome sequencing to assess target/resistance mechanisms. CRISPR/Cas9 and other reverse genetics approaches will be used for target validation.
Primary supervisor: Professor Katherine Andrews
Other supervisor: A/Prof Tina Skinner-Adams, Dr Gillian Fisher
To apply: Contact Prof Katherine Andrews with your CV at k.andrews@griffith.edu.au