Awards

Janine Aucamp of North-West University in South Africa will produce a novel drug screening platform for malaria by building a physiologically-relevant in vitro tissue model of the sinusoidal space of the human liver, which supports the development of liver-stage malaria parasites (sporozoites). Artemisinin-based combination therapies are first-line treatments for malaria but their efficacy suffers from the development of resistance, thus alternative approaches are needed. One approach is to block parasite development in the liver, which can prevent the establishment and symptomatic onset of malaria. They will build three different three-dimensional micro-bioreactor liver models and evaluate how well they can be infected by Plasmodium falciparum sporozoites compared to two-dimensional cultures. They will then test the value of the most promising model for identifying anti-malarial drugs first using two approved drugs and subsequently by screening novel drugs.

Grace Mugumbate of Chinhoyi University of Technology in Zimbabwe will develop new anti-malarial drugs by using a chemogenomics approach for ligand-based and structure-based virtual screening to identify compounds that selectively bind to heat shock proteins of the malaria parasite, Plasmodium falciparum. P. falciparum heat shock proteins are essential for parasite growth and survival, and represent a valuable new target for developing safe and effective anti-malarials. They will use existing chemical and genomic data to produce three-dimensional structures of several heat shock proteins for performing the virtual screens. Machine learning approaches will be used to identify binding ligands and inhibitors that will be validated using enzymatic assays in vitro. Promising hits will then be subjected to structure-based optimization to identify active compounds as leads for further development.

Erick Strauss of Stellenbosch University in South Africa will develop a small molecule inhibitor of an enzyme that helps pathogenic bacteria evade the host immune system and potentially become resistant to antibiotics as a novel treatment for methicillin-resistant S. aureus (MRSA), which is a major public health concern. They discovered a bacterial enzyme, MerA, that neutralizes an anti-microbial compound secreted by immune cells. This prolongs the survival of the bacteria in the host, giving them time to develop mutations that could render them less susceptible to antibiotics. They have identified two different chemical scaffolds that occupy the active site of MerA and will employ a new inhibitor discovery strategy that combines parallel synthesis with an X-ray structure-based binding screen to identify promising MerA inhibitor leads. These leads will be evaluated by in vitro and ex vivo assays for further development.

Lyn-Marie Birkholtz of the University of Pretoria in South Africa will identify gametocytocidal
compounds that specifically prevent human-to-mosquito transmission of gametocytes and block gamete and oocyst formation in mosquitoes as a complementary strategy to help eliminate malaria. Traditionally, anti-malarial compounds have been developed to target asexual blood-stage parasites. However, also blocking parasite transmission is critical for eradication. They developed a platform that can screen multiple sexual stages of the parasite and recently used it to identify ten hit compounds from the Medicines for Malaria Venture (MMV) Pandemic Response Box (PRB), most of which have not previously been tested against malaria-causing parasites. They will validate those hits, optimize them, and analyze their structure-activity-relationship (SAR) and their potential mode of action to identify at least one chemotype as an early lead candidate for further development.

Laurent Dembele of the Université des Sciences, des Techniques et des Technologies de Bamako in Mali will use their cell-based ex vivo phenotypic drug assay to identify approved anti-malarial drugs that are effective also against the neglected malaria-causing pathogen Plasmodium malariae, which has become widespread in sub-Saharan Africa. To eliminate malaria, treatments should be effective for all circulating malaria pathogens. However, current artemisinin-based combination therapies (ACTs) are largely designed to target the historically more prevalent P. falciparum species. They will recruit around 400 patients with uncomplicated malaria in Faladje to determine the P. malariae malaria burden. They will also evaluate the ability of a panel of anti-malarial compounds to destroy cultured P. malariae together with P. falciparum to help guide treatment strategies.

Fortunate Mokoena of North West University in South Africa will couple molecular docking approaches with in vitro and in vivo validation to identify novel inhibitors of Trypanosoma brucei and Plasmodium falciparum, the causative agents of the lethal diseases, African trypanosomiasis and malaria, respectively. Current drugs targeting these pathogens have limited efficacy due to the development of resistance and can cause severe side effects. They will identify a new group of drugs that specifically target parasitic molecular chaperone proteins, specifically heat shock protein 90 (Hsp90), which is an ATPase that helps correctly fold newly synthesized proteins. They will computationally model the structures of Hsp90 from both T. brucei and P. falciparum and prepare a three-dimensional database of inhibitors for virtual screening. The top 30 candidate inhibitors that selectively bind parasitic Hsp90 will be subjected to geometry optimization and induced fit molecular docking, followed by evaluation of their parasite killing activity in vivo.

Elizabeth Kigondu of the Kenya Medical Research Institute will identify natural products that block the resistance mechanism developed by tuberculosis-causing bacteria against existing anti-mycobacterial drugs to help more effectively treat tuberculosis. Tuberculosis (TB) is a highly prevalent and severe disease that has been exacerbated by the emergence of multi-drug resistant TB for which only limited treatments are available. Efflux pumps play a critical role in mycobacterial resistance to two drugs, spectinomycin and rifampicin. They will identify natural products and their derivatives that block these efflux pumps by first searching databases for analogs to published efflux pump inhibitors, and then performing virtual docking experiments to identify those that bind. These will then be tested in drug combinations with spectinomycin and rifampicin for synergistic cytotoxicity and anti-mycobacterial activity.

Gabriel Mashabela of the South African Medical Research Council will develop novel tuberculosis drugs derived from South African medicinal plants by utilizing CRISPR genome editing technology to produce Mycobacterium deficient in essential metabolic enzymes that can be used to screen natural products. Although the majority of approved drugs are of natural origin, most drug-screening approaches use synthetic libraries, which lack diversity. However, natural products contain very low concentrations of bioactive compounds making them difficult to use in traditional drug screens. To address this, they will use CRISPR to reduce the levels of a selection of essential metabolic enzymes, without removing them completely, so that lower levels of bioactive compounds are needed. They will prepare extracts from 100 plants with anti-mycobacterial activity, and perform whole cell screening to identify those with killing activity against the different Mycobacterium mutants. These can then be further optimized for drug development.

The project aims to discover molecular scaffolds that could be forerunners of EAEC therapeutics. Following a small molecule library screen, the team is evaluating hits, determining their mechanisms of action and their potential to be progressed as drug candidates. The group will also apply their anti-biofilm screen to other small libraries with a view to increasing the repertoire of promising leads against EAEC and other neglected enteric pathogens.

This project builds on intra-African and international (pharmaceutical companies, academic institutions) collaborations to identify medicinal chemistry starting points from the screening of target-based chemical libraries against the causative agents of malaria, leishmaniasis and Human African Trypanosomiasis (HAT), also known as sleeping sickness.