The world is facing an enormous and growing threat from the emergence of superbugs that are resistant to most currently available antibiotics. Medicinal Chemistry researchers are collaborating on multiple programs to discover the next generation of antibiotic agents.
This work has attracted funding from the Australian Research Council and the National Health and Medical Research Council, along with support from the Australia-China Special Fund for Science and Technology Cooperation under the International Science Linkages program.
Research topics include:
- Anti-infective agents
- Peptide antibiotics
- Antimalarial agents
- Human African trypanosomiasis and Chagas disease
- Prof Jonathan Baell
- Dr David Chalmers
- Prof Peter Scammells
- Prof Martin Scanlon
- Prof Philip Thompson
- Dr Daniel Priebbenow
President Obama issued a directive in 2014 to accelerate research into understanding the mechanisms of bacterial resistance and the development of suitable countermeasures. Key recommendations in a report to the President advised:
- supporting early-stage chemistry for novel compound libraries
- targeting non-essential bacterial functions to protect patients without selecting for resistance
- searching for narrow-spectrum antibiotics
These principles underpin much of Medicinal Chemistry's research in this area. Fragment-based drug design is used to identify compounds that bind to a target of interest. Novel designed compound libraries are utilised to target enzymes that are key mediators of bacterial virulence. These enzymes cause the formation of disulfide bonds in Gram-negative bacteria and are essential for the correct folding and activity of many virulence factors. Inhibition of these disulfide-bond forming enzymes renders bacteria avirulent, but does not inhibit growth—suggesting that they will not exert strong selection for resistance.
Organism-specific enzymes, such as the mannose transferase enzyme PimA from Mycobacterium tuberculosis, are also being targeted. This enzyme catalyses an important step in the synthesis of the highly unusual mycobacterial cell wall, and is essential for mycobacterial survival. Inhibitors of PimA are likely to have a narrow spectrum of activity.
The problem of drug resistance is not limited to bacterial infections. Medicinal Chemistry is also using fragment-based drug design to develop inhibitors of the integrase enzyme from the human immunodeficiency virus (HIV).
Treatment regimens containing integrase inhibitors have demonstrated superiority over current combination therapies. However, although drugs that inhibit HIV integrase have only been used clinically for a relatively short period of time, resistant strains of HIV have already begun to emerge. Medicinal Chemistry researchers have identified compounds that inhibit integrase through a different mechanism to current drugs, and it is likely that these will have different resistance profiles.
Working in tandem with MIPS Drug Delivery, Disposition and Dynamics, Medicinal Chemistry is interrogating the potential for enhancing the therapeutic utility of the polymyxin antibiotics.
We have developed refined synthetic methods enabling the synthesis of more than 400 variants of this cyclic lipopeptide, allowing us to identify the molecular determinants of antibacterial activity, as well as kidney toxicity—the major dose-limiting side effect of these antibiotics.
This knowledge is also being harnessed into studies of other natural product lipopeptides, with a view to exploiting their capacity for activity against multi-drug-resistant bacteria.
Malaria is the world's most prevalent parasitic disease. It is caused by parasites of the genus Plasmodium, of which Plasmodium falciparum is the most lethal. There are approximately 200 million cases of malaria each year, resulting in more than 600 000 deaths, mostly caused by Plasmodium falciparum infections.
The spread of drug-resistant parasites has rendered most of the current antimalarial treatments ineffective. As malaria prevention and treatment become increasingly difficult, there is an urgent need for next generation antimalarial agents with novel modes of action. This is the focus of Medicinal Chemistry's research in this area.
Apical membrane antigen 1 (AMA1) is an integral membrane protein involved in parasite invasion that is being studied as a potential target of new antimalarial drugs. A fragment-based drug discovery approach is being undertaken to develop inhibitors of this protein as potential antimalarial agents.
Plasmodium falciparum metalloaminopeptidase enzymes, which play crucial roles in the symptomatic erythrocytic stage of infection, are also being pursued as antimalarial targets. These enzymes mediate the degradation of haemoglobin into free amino acids that are essential for parasite growth and development. A structure-based drug design approach is being employed to develop inhibitors of these enzymes as potential antimalarial agents.
Human African trypanosomiasis and Chagas disease
Human African trypanosomiasis (HAT), more commonly known as sleeping sickness, is a vector-borne parasitic disease caused by infection with either Trypanosoma brucei gambiense or Trypanosoma brucei rhodesiense. The World Health Organization estimates there are 30 000 cases of HAT in Africa, which has significant socioeconomic impact.
Chagas disease is caused by Trypanosoma cruzi and transmitted by the bite of the Assassin Beetle. More than 10 million people are infected with this parasite, and this is associated with 14 000 deaths from Chagas disease annually. The most important parasitic disease in the Americas, Chagas disease is a bigger health problem in the region than malaria. In Brazil alone, an estimated $1.3 billion is lost in wages and productivity each year due to Chagas disease.
Both diseases are currently very poorly treated. Medicinal Chemistry is working on an array of exciting drug discovery projects targeting these parasites.