Combatting the rise of the Superbug

We live in a time where we expect to be able to visit the doctor and get a script that will clear up infections. Sicknesses that might once have killed us are now cured within days with antibiotics but what if our go to medications stopped working so well? LIMS researchers are working on this problem.

It's often reported that the likely result of using antibiotics too often is that soon, there will be infections that will be so resistant to our usual treatments they will become life threatening. According to the ABC, Health Minister Sussan Ley says that Australia has one of the highest rates of antibiotic use in the world, and the World Health Organisation advises that antibiotic resistance is a serious threat to our health.

Dr Belinda Abbott and her team of research students are using medicinal chemistry to develop new ways to treat bacterial infections. Simply put, they make new molecules to see if they can kill bacteria.

Medicinal chemistry involves the design, synthesis and development of the molecules we need in order to understand, prevent and treat disease. We use organic chemistry to make novel compounds and then test them in biological assays, which are either undertaken in our lab or by collaborators.

As a result, we can grow our understanding of how changes to a synthetic compound affects a biological target, which is usually an enzyme or receptor that is important for a cell to live.

You've said that multi-drug resistant bacteria represents a significant public health threat. How big a threat are 'Superbugs'?
The discovery of antibiotics in the early 20th century meant that common bacterial infections, causing illnesses such as pneumonia, urinary tract infection, gonorrhoea and tuberculosis, could be treated relatively easily. Surgery, dentistry and childbirth became much safer.

Antibiotic resistant bacteria or 'superbugs' are very difficult to treat, as the current drugs we have for them no longer work. We risk returning to a time where bacterial infection may result in severe disability or death, which has immense implications for the world we live in. The World Health Organisation already estimates that hospital patients infected with resistant bacteria have a death rate which is about twice that of patients with non-resistant bacterial infection.

How does bacteria become drug resistant?
Bacteria reproduce much faster than we do. During this process, bacterial genes can change and so the corresponding bacterial proteins can change. Such changes may mean an enzyme or receptor is no longer affected by an antibiotic drug or the bacteria is better able to expel or inactivate the drug. Bacteria are also able to transfer genes to one another. So a mutated gene which results in antibiotic resistance can be shared and spread between neighbours.

Bacteria are very good at evolving to ensure their survival, however this is problematic if you are the human who is infected by them.

How does your work attempt to fix the problem?
Developing novel antibacterial molecules to inhibit targets that have not previously been studied in bacteria is currently an important focus of our group. It is critical to develop new treatments for bacterial infections with different strategies to those used by current drugs.

We are currently working on developing inhibitors against two different bacterial enzymes.

The first of these targets is dihydrodipicolinate synthase (DHDPS) which catalyses the first step of the biosynthetic pathway which produces meso-DAP, a molecule which bacteria need to build their cell walls. If we can stop this enzyme, then the bacteria can't make meso-DAP and so they can no longer grow and divide.

The second project is trying to halt the action of disulfide bond (Dsb) forming enzymes, which are bacterial machinery to folds many of the toxins and surface proteins required for virulence in a range of pathogenic bacteria including meningitis and gonorrhoea. Bacteria without this ability are no longer such a threat to our health.

We take a lead compound, which shows some ability to inhibit our target, and use organic chemistry to modify it. The aim is to build a molecule which is highly potent and specific against the bacteria. If we can make such a compound, it will be followed by much more research to ensure it is safe for human medicine – our work is at the very forefront of the drug discovery process.

This article was originally published in the La Trobe University Knowledge Blog.

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