Faculty of Natural and Agricultural Sciences
School of Biological Sciences
Department of Biochemistry
Selected Highlights from Research Findings
Millions of people die as a result of malaria every year. The Malaria Research Group focused on the comprehensive investigation of the biological response (functional genomics) of the malaria parasite to drug-induced polyamine depletion, which results in growth arrest of the parasite (cytostasis), but not death. This includes the analyses of the parasites transcriptome, proteome and metabolome, and biological validation of the observed effects. Polyamines provide the parasite with essential polycationic metabolites to allow successful DNA replication and therefore cellular growth and division. The aim of one of the research group’s projects, Functional genomics investigations of perturbed malaria parasites, was to develop multilevel, global response analyses of the malaria parasite after perturbation with inhibitors as an aid to identify and validate anti-malarial drugs and drug targets. As far as could be determined, this work provided the first report using such a comprehensive functional genomics approach to study the response of a multistage organism like the malaria parasite to an external perturbation. Results showed that cytostasis upon polyamine-depletion produce a generalised transcriptional arrest, a phenomenon that could include other organisms/systems. The researchers provided conclusive evidence for transcriptional level regulation in the malaria parasite in response to external perturbations, in addition to the widely reported post-transcriptional regulation. This contributes a new dimension to our understanding of the regulation of gene expression in the malaria parasite. The researchers also observed highly specific compensatory biochemical processes that were induced in response to the polyamine-depletion at the transcriptome level and comprehensively biologically validated in both the proteome and metabolome. The work provided specific information on the role of polyamines in the life cycle of the malaria parasite and therefore enhances our understanding of and provides insights into the molecular mechanisms and biochemical processes controlling polyamine metabolism/homeostasis. Ultimately, the research group contributed to the validation of polyamine metabolism as an anti-malarial drug target. This expertise is now established as part of a functional genomics core expertise group of the South African Malaria Initiative for use in drug discovery endeavours
Contact person: Dr L Birkholtz.
The aim of this research project was to identify and design mechanistically novel inhibitory compounds using in silico structure-based approaches aimed at the polyamine metabolic pathway. The malaria parasite requires synthesis of polyamines for parasite growth, replication and survival. Polyamine biosynthesis in the parasite differs substantially from the human host and is controlled through the action of a unique bi-functional enzyme. Computer-based strategies (in collaboration with the Bioinformatics and Computational Biology Unit of the Department of Biochemistry) were used in the design of mechanistically novel inhibitors of one of these proteins, spermidine synthase. High-quality three-dimensional protein structures were produced and used in the design of dynamic pharmacophores, which are consensus structures representing the essential chemical elements for inhibitors of this specific malaria protein. Small chemical compounds fitting these descriptions were identified through the virtual screening of chemical libraries. One of the nine compounds tested had a significant inhibitory activity and is also a novel inhibitor for this enzyme. Further studies are in progress to improve the properties of this compound to fit the general properties of a drug lead that can proceed to the next level in the anti-malarial drug discovery process. This finding provides a platform for the application of this strategy in drug discovery studies of this and other identified proteins
Contact person: Prof AI Louw.
Approximately one and half million patients who suspect that they have tuberculosis (TB) annually report to clinics in South Africa. Of every 100 patients, 35 eventually turn out to suffer from active TB. Of these, 20 can typically be diagnosed inexpensively within three days, using microscopy of lung sputum samples. A six-month combination treatment is commenced with the TB patient becoming non-infective within a week, thus no longer posing a threat to the medical staff at the clinic/hospital and the community to which they return. The problem is the remaining 80 patients who initially tested negative on smear microscopy. With no means of knowing how infective they are, they are hospitalised for a week. Typically, symptoms prevail in 45 patients, who are then subjected to a microbiological growth test from sputum, the results of which only become known after eight weeks, with a 30% underestimation of active TB when it co-occurs with HIV infection. During this period, TB-HIV co-infected and extreme drug-resistant patients die during their two-month stay in hospital, while putting medical staff at extreme risk of contracting drug-resistant TB. The MARTI serodiagnostic test for TB is an all-South African idea patented in 2005 by the University of Pretoria and published by the TB research team of Prof Jan Verschoor in 2008. It is a biosensor test that detects mycolic acid antibodies as surrogate markers of active TB. It is not affected by HIV/AIDS and delivers an answer on the same day as sampling, thereby doing away with the need for hospitalisation. It is the most accurate serodiagnostic TB test in high-burdened HIV and TB disease populations to date, due to the nature of the antigen and the high-technology way in which the antibodies are detected. The MARTI test only requires a droplet of blood from the patient. By not being restricted to sputum samples, the MARTI test may turn out to be the only test that can accurately determine extrapulmonary TB, which typically occurs in children and immune-compromised individuals, such as HIV/AIDS patients. The MARTI test could lead to the initiation of early treatment, stop transmission of TB from the day of reporting to the clinic, and reduce the emergence of drug resistance. The MARTI test is currently supported by South Africa’s Biotechnology Regional Innovation Centres for development for the market, and has been nominated as a flagship project of the India-South Africa bilateral research agreement on health and biotechnology of 2009
Contact person: Prof JA Verschoor.
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