Our Research

Reversing multidrug resistance with efflux pump inhibitors

Antibiotic-resistant infections cost the Australian government billions of dollars a year. Without new strategies to address drug resistance, we are heading for a post-antibiotic era where small injuries and minor infections will once again be fatal. Central to resistance is the expression of efflux pumps, through which bacteria extrude drugs. These efflux pumps are also implicated in bacterial virulence and biofilm formation. Moreover, functional efflux pumps are necessary for the selection of drug-resistant bacteria.

Despite their crucial role in bacterial pathogenesis and multidrug resistance, there are currently no inhibitors of drug efflux pumps in clinical use.

Due to the critical role that drug efflux pumps play in resistance and virulence efflux pump inhibitors (EPIs) will (a) synergise with currently used antibiotics, (b) restore the efficacy of antibiotics to which resistance has arisen, (c) reduce the emergence of drug-resistant pathogens, (d) reduce the ability of pathogens to infect the host as the inhibition of efflux attenuates the bacterium and (e) prevent the development of highly drug resistant biofilms. This project aims to identify and develop new inhibitors against drug efflux pumps from Gram-negative bacteria.

Keywords: multidrug resistance, antibiotics, pathogenic bacteria, natural products.

If you are interested in this research please contact Dr Rietie Venter

Plumbagin

Plumbagin is a phytochemical from Plumbago indica that can inhibit antibiotic efflux

Multidrug resistance and virulence of pathogenic bacteria

‘Superbugs’ are costing the medical and veterinary industries millions of pounds a year and antibiotic resistance is one of the world’s most pressing health problems. One such a superbug is the gram negative bacterium P. aeruginosa. This pathogen is associated with a range of life-threatening hospital-acquired infections and is the main cause of mortality in patients with cystic fibrosis. P. aeruginosa infections are hard to treat since this organism displays resistance against multiple classes of antimicrobials. Central to the antibiotic resistance of this bacterium is the expression of drug efflux pumps which lowers the concentration of drugs inside the cell to sub-toxic levels.  It is also becoming increasingly evident that multidrug transporters play a role in bacterial pathogenesis.

Multidrug resistance

P. aeruginosa isolated from the lungs of a Cystic Fibrosis patient. The green colour is due to the virulence factor pyoverdine

This project aims to provide a characterisation of drug efflux proteins from P. aeruginosa. We strive to understand the molecular mechanism of substrate transport and the wider role of efflux proteins in virulence and infection.

The mechanisms that govern drug resistance and virulence are conserved between bacteria, fungi and parasites. Hence, the insight gained from this research will help us devise new drugs and therapies to combat infection by superbugs, pathogenic fungi and even parasites linked to malaria.

Keywords: multidrug resistance, drug efflux protein, pathogenic bacteria, virulence

If you are interested in this research please contact Dr Rietie Venter

Iron acquisition proteins as drug targets in pathogenic bacteria

The emergence of ‘superbugs’ which are becoming more virulent and more resistant against drugs is one of the world’s foremost health problems. The available antibacterial treatments are becoming increasingly ineffective, making the discovery of new treatments and therapies urgent. An emerging field of fighting infection is the targeting of bacterial iron acquisition. Iron is crucial for the survival of pathogens as well as being an essential constituent of virulence and biofilm formation. Ferrous iron is acquired by the Feo transporter. Despite the vital role of the Feo proteins in the survival and virulence of pathogens, our knowledge about this transporter system is still in its infancy. This project aims to characterise the molecular mechanism of transport and regulation by the Feo proteins from the pathogen P. aeruginosa using molecular, biochemical and biophysical techniques.

FeoB

FeoB is predicted to form a Cys-lined, GTP-gated pore

A better understanding of the Feo system might help us devise inhibitors for this iron acquisition system and ultimately starve the pathogen from a vital nutrient as well as prevent the formation of highly drug resistant bacterial biofilms.

Keywords: pathogenic bacteria, membrane protein, iron transport, virulence

If you are interested in this research please contact Dr Rietie Venter

Novel Treatments Against Antibiotic Resistant Biofilms

The default state for >99.9% of all bacteria is the biofilm state. Biofilms are communities of bacteria that are embedded in a slime that protects the bacteria from our immune system and antibiotic treatments. As a result, bacteria residing in biofilms are up to 1000-fold less sensitive to antibiotic treatment than “free-swimming” bacteria. Biofilms can form on any living or non-living surface. This versatility makes biofilms responsible for more than 80% of all infectious diseases. Importantly, biofilms are implicated in almost all chronic infections, such as chronic wound infections, cystic fibrosis lung infections, bone infections, otitis, sinusitis, medical device infections, etc. The hallmark of biofilms, their inherent tolerance to antibiotics, contributes substantially to the worldwide problem of drug resistance.

Our research aims to develop novel treatment strategies against biofilms.

We are a team of interdisciplinary researchers (chemistry, pharmacy, biology, and bio-engineering) dedicated to make a difference for the community. One of our strengths is that we work hand in hand with other disciplines (e.g. surgeons and other clinical specialists) both nationally and internationally to get the most of our research. This way we are not confined to the lab, but ultimately strive to apply our research findings out where it matters most - in real life.

Our work is funded in part by the National Health and Medical Research Council (NHMRC) and employs cutting-edge microscopy techniques (Figure 1) to get a better understanding of the biofilm architecture. Using novel nanomedicine approaches we develop new medicines to treat some of the most debilitating diseases.

If you are interested in this research area please contact Dr Nicky Thomas

Keywords: Biofilm, nanomedicine, antibiotic resitance, correlative light/electron microscopy (CLEM)

Electron

Figure 1: Electron micrograph of biofilm formed by the pathogen Staphylococcus aureus (“golden staph”). Courtesy K.Richter/N.Thomas.

Natural Products Research

We have a focus on collaborative research with Australian Aboriginal communities and traditional healers examining the antimicrobial and anti-inflammatory activity of plant extracts and plant compounds used in traditional medicine. Our research involves field work, plant extraction, testing of plant extracts for pharmacological activity, activity-guided fractionation of plant extracts and the isolation and structural determination of biologically active compounds from plants.

Natural product chemistry techniques used include solid phase extraction, column chromatography, thin layer chromatography (TLC), centrifugal radial TLC, high performance liquid chromatography (HPLC), nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry.

If you are interested in this research area please contact Dr Sue Semple

Plant Material

David, Sue and Farren collecting plant material

Gut Interaction Group

Chemotherapy-induced mucositis

Chemotherapy targets all rapidly dividing cells to cause cells death, whether they be cancer cells, or normal cells, such as epithelial or blood cells.  Epithelial cells that line the gastrointestinal tract are severely damaged by chemotherapy, resulting in a variety of dysfunction, including diarrhoea.  We are working with both cell culture and animal models to investigate ways to prevent damage to normal cells caused by chemotherapy.  Animal models have been developed in rats (tumour and non tumour bearing) and mice (non tumour bearing only).

If you are interested in this research area please contact Dr Andrea Stringer

Host-microbe interactions research

We have cell culture models to investigate host-microbe interactions under controlled conditions.  We use normal epithelial cells and microbial biofilms to initiate these interactions, and we are investigating the effects of exposure to chemotherapy agents, other pharmaceutical agents and metabolites, probiotics, prebiotics, and various chemical compounds. As the gut microbiota are considered to play a key role in maintaining health, it is important to understand how these common agents can affect the microbiota, and subsequently the host. Experiments in these models are then translated into animal models to investigate the effects in a multi-organ system model.

Industry-linked projects are also undertaken within the group.

If you are interested in this research area please contact Dr Andrea Stringer 

Areas of study and research

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