Fighting to eradicate major infectious diseases

At GRIDD, we’re looking into the world’s most serious infectious diseases and exploring ways to overcome them for good. Such diseases include tuberculosis, neglected tropical diseases and malaria, which affects millions of people across the globe each year.

TUBERCULOSIS

GRIDD Foundation Director Professor Ronald Quinn is pursuing a cure for tuberculosis (TB) and has had some encouraging early results. TB is one of the top 10 causes of death worldwide. Drug resistance has also been a major issue for those trying to help sufferers.

Professor Quinn and his team are building a pipeline partly based on high-throughput screening by the AstraZeneca Company, which tested our NatureBank’s library of fractions on a highly virulent pathogenic strain of TB. They found several hundred active fractions (a partially purified mixture of natural products)had an impact on the TB strain.

A second input to the pipeline uses the technology of fragment-based drug discovery. Using this approach, the Quinn team has identified pure compounds, which, when joined together synthetically, may be developed to produce a drug to combat TB.

The findings aim to translate fundamental lab research into the clinical setting, where candidate drugs are tested and if all goes well, developed into a commercial product. Because of the inherent possibilities of this research, the early findings have not yet been published.

MALARIA

Malaria is one of the world’s most significant infectious diseases, killing a child every two to three minutes. This means more than 1,000 children die of malaria every day.

GRIDD researchers play a key role in the fight to eradicate malaria. Professor Kathy Andrews’ team of biomedical scientists are working to identify new drugs to prevent and treat this major parasitic disease.

Professor Andrews and her team work with national and international collaborators to identify weaknesses in the malaria parasite and then develop new malaria drug candidates that may help to combat drug resistance and eradicate malaria.

New drugs for malaria urgently needed

Malaria prevention and treatment currently relies on antimalarial drugs and public health measures, such as insecticide-treated mosquito nets and indoor residual spraying. A broadly effective vaccine is not yet available and while current treatment drugs are effective, malaria parasite drug resistance is a major issue that threatens recent reductions in malaria cases and deaths. Drugs to prevent malaria from occurring are limited.

A major goal of the Andrews team is to help develop effective new drugs to prevent malaria. With funding from Australian National Health and Medical Research Council, the team collaborates with Australia’s Commonwealth Scientific and Industrial Research Organisation (CSIRO) and the world’s leading not-for-profit malaria drug development organisation, the Medicines for Malaria Venture.

INFECTIOUS AND NEGLECTED TROPICAL DISEASES

Impact of malaria and neglected tropical diseases

Neglected tropical diseases (NTDs) (including Chagas disease, leishmania and human African trypanosomiasis) and malaria belong to a diverse group of primarily parasitic diseases that occur in tropical and subtropical regions throughout the world. These diseases affect more than one billion people, and impact on developing economies to the tune of millions of dollars every year. Collectively, NTDs and malaria kill several million people every year. Malaria alone is responsible for almost 500,000 deaths a year.

Therapeutic limitations

Current therapeutics have limited effects across all stages of these diseases and many have severe side effects, some life threatening. Drugs that are effective are also at risk of resistance development, threatening to lose their efficacy in the future. The Avery team is tackling these problems on a number of different fronts to improve our understanding of NTD biology and to discover new drugs to treat NTDs.

The challenge

Professor Vicky Avery’s lab has investigated parasites that have human and insect hosts. It is essential the lifecycle of each parasite can be replicated in the lab and the parasite retains infectivity when used experimentally. Two critical limiting factors for NTD drug discovery, prior to testing compounds, is the establishment of highly reproducible culturing systems and production of large quantities of the different parasite stages for screening purposes. The Avery lab has succeeded in overcoming these limiting factors for all the parasites they are working on.

Innovative technologies and strengths

The Avery lab provides the key chemical starting points for the drug discovery and development pipeline. From concept, through to preclinical drug development, the team provides sophisticated assays with ever-increasing complexity and functionality, using the most advanced high-throughput and high-content imaging systems available for drug discovery in Australia. An essential component of the research is ensuring discovery platforms accurately reflect and where possible, mimic, the in vivo situation. This increases the likelihood of finding compounds that will translate in vivo and work effectively in people. The comprehensive imaging platforms span multiple lifecycle and developmental stages of the parasites, and so are highly informative.

Utilising high-throughput screening (HTS) to determine how effective a compound is at killing the parasites, the Avery lab rapidly and reproducibly evaluate many 100,000s of compounds in a short time. Their capabilities and industry-based approach has provided the foundation for numerous long-term and fruitful collaborations throughout the world.

Achievements

Successful drug discovery requires commitment and a highly collaborative and cross-disciplinary environment.

The Avery lab has contributed significantly to NTD drug discovery over the past 10 years. They designed the first HTS assay to identify compounds that inhibit growth of the parasites causing Human African Trypanosomiasis (sleeping sickness).

Professor Avery’s team were the recipients of the Medicines for Malaria venture (MMV) MMV International Drug Discovery Project of the Year 2007 for innovative use of technology to identify new anti-malarials, and again in 2013 for their contribution to the clinical candidate, MMV390048. Many of the compounds they have identified or profiled during development have now progressed to clinical trials.

Professor Avery is passionate about this research. ’I speak for my entire team when I say it is a great feeling to know we are making a difference. Our research has the potential to have a significant impact and help some of the world’s poorest people overcome devastating diseases,’ she says. Professor Avery continues to work in collaboration with the Medicines for Malaria venture; Drugs for Neglected Diseases initiative and more recently with the Global Health Initiative (GHIT Fund—Japan).

Researcher spotlights

Dr Tina Skinner Adams

Research Leader Dr Tina Skinner Adams works in the field of antiparasitic drug discovery and drug target identification, with a goal to improve the lives of those at risk of parasite infection. Her primary research focus is the discovery and investigation of new drugs to treat giardiasis, and treat and prevent malaria. Dr Skinner-Adams holds two National Health and Medical Research Council project grants and works with four PhD candidates who are focused on malaria and giardiasis. She and her team use techniques including high-content imaging, chemical genomics and reverse molecular biology, to identify, investigate and optimise the activity and selectivity of compounds with anti-parasitic activity.

Associate Professor Andreas Hofmann

Associate Professor Andreas Hofmann’s research is at the interface of chemistry, biology and related technologies, with a clear focus on protein structure-function in the context of novel therapeutics for infectious and neurodegenerative diseases. He and his team have identified novel parasite-derived antigens that are being tested in immunisation trials with international collaborators. His laboratory has received research funding from the Australian Research Council, the National Health and Medical Research Council and the Rebecca L Cooper Medical Research Foundation. His laboratory’s research has been published in the FASEB Journal and Lancet Infectious Diseases.

Dr Melissa Sykes

Postdoctoral fellow and Early Career Research Leader Dr Melissa Sykes in Professor Avery’s team plays a pivotal role in a collaborative lead optimisation project to find lead molecules against the protozoan Trypanasoma cruzi. This parasite is the causative agent of Chagas disease, affecting 6-7 million people worldwide (World Health Organisation statistics). The research, which is supported by an Australian Research Council (ARC) Linkage grant, has identified a number of efficacious compounds that suppress T. cruzi infection in vitro using image-based technology. Dr Sykes received the Griffith University 2016 Pro-Vice Chancellor (Sciences) Research Excellence Award.

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