Australasian Science Magazine

Clusters of the bacterium Staphylococcus aureus protected by a biofilm.

By Katharina Richter

Antibiotic resistance is expected to kill more people than cancer and diabetes combined, but a new approach aims to penetrate the biofilms that protect bacteria from antibiotics.

The rise of multi-resistant bacteria is one of the greatest risks to human health today. Recently the UK’s Review on Antimicrobial Resistance predicted that ten million people will die per year by 2050 due to infections caused by anti­biotic-resistant superbugs, which is more than the number of people dying from cancer and diabetes combined.

Bacteria have established subtle mechanisms to evade the immune system and become resistant to antibiotics. One way they do this is by forming biofilms. Biofilms are clusters of bacteria embedded in a self-produced slime. This matrix protects the bacteria against both immune attack and medical treatments.

Biofilms can be envisaged as a fortress comprising thick walls that antibiotics typically cannot penetrate. Within this fortress the bacteria can multiply and adapt to their environment, making it very hard to kill them.

Biofilms are found from head to toe. According to the US National Institutes of Health they account for more than 80% of microbial infections in the human body, including dental plaque, sinusitis, wound infections, urinary tract infections and catheter infections.

Biofilms can have lethal consequences when medical therapies fail to eradicate them, such as in cases of:

• cystic fibrosis, where biofilms are responsible for recurring infections of the lungs, resulting in irreversible damage;
• endocarditis, an inflammation of the inner layer of the heart; or
• an infection of implants like artificial heart valves.

No matter how sophisticated implants, catheters, medical devices or tissue engineering constructs are, biofilms are able to form almost everywhere. Yet the biofilm state was not known when the majority of antibiotics were discovered, and as a result all established antibiotics were based on studies of single bacteria. However, eradication of the bacteria in biofilms requires antibiotic concentrations up to 1000-fold higher than single free-living bacteria, and hence they can cause persistent and recurring infections.

While antibiotics seemed to be able to cure every infectious disease half a century ago, the current situation is devastating. According to the federal Department of Health, Australia has one of the highest rates of antibiotic use worldwide, with more than 23 million antibiotic prescriptions supplied to more than 45% of Australians in 2013. The overuse and incorrect use of anti­biotics in both humans and livestock can expose bacteria to subtherapeutic concentrations of antibiotics, enabling bacteria to evolve and adapt to existing antibiotic treatments. They are now becoming increasingly resistant to last-resort antibiotics.

How can we battle these superbugs when established medical care does not defeat them anymore?

One approach involves developing compounds whose mechanism of action is distinctively different from those of traditional antibiotics. In tandem with this, novel compounds are also required to tackle bacterial biofilms. These can kill the bacteria by attacking and disrupting the thick slime layer so that treatments can enter the fortress and fight against bacteria from the inside.

Another approach is to interfere with the ability of bacterial cells to communicate with each other within the biofilm fortress, enabling a streamlined and coordinated behaviour of the entire bacterial community. If this signalling is interrupted, either by degrading the signal molecules or interrupting the perception of signals, the defence of the bacterial community against therapeutics would be weakened.

Another strategy is to block certain proteins and receptors on the bacterial surface in order to attenuate bacterial virulence. Small molecules, novel compounds in smart drug-delivery systems and innovative coatings for medical devices offer the potential to prevent attachment of bacteria, alter gene expression and inhibit or disrupt biofilm formation.

A further approach is the therapeutic use of bacteriophages. These viruses specifically target and fight single bacteria without causing harm to the human body. Despite the huge potential of phage therapy against multi-resistant superbugs, their use is controversial and currently only approved in a handful of countries worldwide. However, clinical trials taking place in Adelaide and other cities around the world might open the use of this new therapy in the near future.

Another novel treatment targets bacterial metabolism. In particular, the metabolism of iron is vital for bacterial growth, survival and pathogenesis.

My research has identified a novel treatment combining two compounds that work synergistically together. The first compound captures nutrients in the environment around biofilms, thereby cutting off essential food paths for the biofilm fortress and leading to its starvation. Subsequently, the biofilm opens specific gates in order to allow nutrient sources into the fortress. The second compound in my strategy is a “Trojan horse” that mimics a preferred food source of bacteria but has biofilm-killing properties. When this is allowed to enter the fortress, biofilms can be conquered and bacteria defeated.

With this new treatment I am specifically looking at how to combat chronic sinus infections. Chronic sinusitis is highly prevalent in the community, affecting one-sixth of Australians irrespective of gender, nationality or age. The available therapies are mainly based on long-term treatment with antibiotics, but many people suffer from recurrent sinus infections due to antibiotic-resistant superbugs. Surgery is often the only remedy for the treatment of chronic sinusitis.

To avoid relapse due to bacteria hiding in the biofilm, I have developed a drug-delivery-system that releases the two compounds at the site of infection, so bacteria starve and die. The treatment is topically applied in the sinuses rather than taken as a tablet. This produces fewer side-effects, less systemic effects throughout the body and less interactions with other compounds or food. Essentially, as this novel treatment does not rely on traditional antibiotics, we have not encountered any bacterial resistance yet.

So far my results have been very promising and show that this approach is an efficient and safe way to kill bacteria in their biofilm fortress. The University of Adelaide’s Ear Nose and Throat Surgery Department is proposing The Queen Elizabeth Hospital as the base for the first human trials.

While the current focus is on chronic sinusitis, a successful clinical trial will hopefully lead us to further refine the treatment so it can eventually be used to treat people suffering from a broad range of chronic infections.