Targeting The Unmet Global Medical Need Caused By Gram-negative 'superbugs': From Antibiotic Discovery To Novel Therapeutic Strategies
Funder
National Health and Medical Research Council
Funding Amount
$697,209.00
Summary
Bacterial ‘superbugs’ present a significant global medical challenge. ‘Old’ polymyxins are the only antibiotics against Gram-negative ‘superbugs’ but with limited pharmacological information available. In the next 5 years, as a pharmacologist I will continue re-developing polymyxins and discovering novel antibiotics against these problematic bacteria. My research targets the “Bad Bugs, No Drugs” disaster highlighted by the Infectious Diseases Society of America and the World Health Organization.
Towards Optimising Dosing Of The 'old' Antibiotic Colistin Methanesulphonate: Enhancing Efficacy And Reducing Resistance
Funder
National Health and Medical Research Council
Funding Amount
$266,500.00
Summary
The global problem of multidrug-resistant bacteria is a major clinical challenge. In cystic fibrosis (CF) patients, the bacteria pseudomonas shows significantly high resistance to the commonly used antibiotics and is a major cause of death. As a consequence, interest in an old antibiotic, colistin, has been rekindled after 40 years on the shelf. The safety of intravenous colistin has been demonstrated in several clinical trials. However, based on our preliminary studies in CF patients, the curre ....The global problem of multidrug-resistant bacteria is a major clinical challenge. In cystic fibrosis (CF) patients, the bacteria pseudomonas shows significantly high resistance to the commonly used antibiotics and is a major cause of death. As a consequence, interest in an old antibiotic, colistin, has been rekindled after 40 years on the shelf. The safety of intravenous colistin has been demonstrated in several clinical trials. However, based on our preliminary studies in CF patients, the current dosage regimen where colistin is given three times a day does not achieve high enough concentrations to kill the bacteria. The studies proposed in this project will address the safety, effectivenss and impact on development of resistance of larger doses of intravenous colistin given once or twice daily. We propose that such dosing strategies will yield more effective usage of this promising 'old' antibiotic.Read moreRead less
Towards Reducing Resistance And Haematological Toxicity Of Linezolid
Funder
National Health and Medical Research Council
Funding Amount
$135,825.00
Summary
Multi-drug resistance in bacteria is increasing at an alarming rate. We have diminishing therapeutic options, and there are few antibiotics in the drug development pipeline that offer much hope. It is therefore important that we look towards ways of further optimising the use of antibiotics that we currently have available. An important last line of defense drug, linezolid, has been available in Australia for less than 2 years and already resistance is occuring. In addition, with broader use of ....Multi-drug resistance in bacteria is increasing at an alarming rate. We have diminishing therapeutic options, and there are few antibiotics in the drug development pipeline that offer much hope. It is therefore important that we look towards ways of further optimising the use of antibiotics that we currently have available. An important last line of defense drug, linezolid, has been available in Australia for less than 2 years and already resistance is occuring. In addition, with broader use of this drug outside clinical trials, there has been an increasing concern over its toxicity to important blood cells. We seek to better understand the determinants of linezolid resistance and toxicity, so that novel dosing strategies may be developed to optimise its use (reduce toxicity and enhance efficacy) thereby extending the usefulness of this last line of defense antibiotic.Read moreRead less
Targeting NDM-producing ‘superbugs’: Optimising Novel Combinations With ‘old’ Polymyxins Using Pharmacological, Molecular Imaging And Systems Biology Approaches
Funder
National Health and Medical Research Council
Funding Amount
$582,732.00
Summary
Rapid global spread of so-called NDM-producing bacterial ‘superbugs’ is presenting a major medical challenge. Without new antibiotics under development, polymyxin is becoming the only effective antibiotic. Unfortunately we recently revealed that treatment with polymyxin alone can rapidly lead to resistance in NDM-producing ‘superbugs’. This project will employ new tools to optimise rational polymyxin combinations, thereby providing urgently needed information to clinicians for treating these ver ....Rapid global spread of so-called NDM-producing bacterial ‘superbugs’ is presenting a major medical challenge. Without new antibiotics under development, polymyxin is becoming the only effective antibiotic. Unfortunately we recently revealed that treatment with polymyxin alone can rapidly lead to resistance in NDM-producing ‘superbugs’. This project will employ new tools to optimise rational polymyxin combinations, thereby providing urgently needed information to clinicians for treating these very problematic infections.Read moreRead less
Novel Therapeutic Strategy Against Multidrug-resistant Gram-negative Bacteria
Funder
National Health and Medical Research Council
Funding Amount
$349,823.00
Summary
In the past two decades, there has been a marked decline in discovery and development of new antibiotics while there has been a remarkable increase in resistance to the currently available antibiotics. The growth in the number of resistant bacteria and lack of antibiotics available for treatment is very significant with gram-negative bacteria, such as Pseudomonas aeruginosa, Acinetobacter baumannii and Stenotrophomonas maltophilia. Colistin, an old antibiotic that has been used little over the l ....In the past two decades, there has been a marked decline in discovery and development of new antibiotics while there has been a remarkable increase in resistance to the currently available antibiotics. The growth in the number of resistant bacteria and lack of antibiotics available for treatment is very significant with gram-negative bacteria, such as Pseudomonas aeruginosa, Acinetobacter baumannii and Stenotrophomonas maltophilia. Colistin, an old antibiotic that has been used little over the last 40-50 years, has been 'taken off the shelf' and is now being used as a last line of defence to treat people with infections caused by these bacteria. Clearly, doctors and their infected patients will be in an even more precarious position than currently exists if resistance to colistin increases. We have discovered a novel therapeutic strategy that is able to reverse colistin resistance in P. aeruginosa. The studies proposed in this project will investigate this novel strategy across a range of multidrug-resistant bacteria and provide the information essential for rational use in patients. We propose that such a novel therapeutic strategy will provide a powerful weapon for the war on these 'superbugs'.Read moreRead less
A National Centre For Antimicrobial Stewardship: Using A One Health Approach
Funder
National Health and Medical Research Council
Funding Amount
$2,601,801.00
Summary
The emergence of antimicrobial resistance is a serious worldwide problem. The National Centre for Antimicrobial Stewardship will use a One Health approach to address antibiotic use in both humans and animals. We will focus on hospitals, aged care, and general practice. In animal health, we will investigate links between antibiotic use in animal production and resistant bacteria, and evaluate usage in companion animals. The aim is to promote appropriate antibiotic use in animal and human health.
Integrative Systems Pharmacology, Neutron Reflectometry And Molecular Dynamics Approaches To Unravelling The Interactions Between Polymyxins And Bacterial Membranes
Funder
National Health and Medical Research Council
Funding Amount
$968,005.00
Summary
Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter baumannii are among the 6 top-priority dangerous ‘superbugs’ causing life-threatening infections worldwide. This study will employ a multi-disciplinary approach to decipher the complex interactions of polymyxins with the membranes of these three ‘superbugs’ and to discover novel antibiotics with superior efficacy. This innovative project targets the urgent unmet global medical crisis due to antibiotic resistance.
The Development Of Novel Antibacterials Targeting Clostridium Difficile Infections
Funder
National Health and Medical Research Council
Funding Amount
$750,546.00
Summary
Clostridium difficile is a bacterium associated with infections in the gut which may result in mild to severe diarrhoea and inflammation of the colon. These infections are an increasing problem for hospitalised patients in the US, the EU and Australia. We have been very successful in the past at developing new drugs to treat external infections caused by resistant strains of bacteria, for example, golden Staph. We now aim to develop our drugs to treat C. difficile infections in the gut.
Redefining Antibiotic Dosing To Reduce Bacterial Resistance
Funder
National Health and Medical Research Council
Funding Amount
$474,513.00
Summary
>3000 Australians die every year from severe infections (nearly 3-fold higher in number than our annual road toll). These treatment failures are due to sub-optimal antibiotic dosing from a poor understanding of why concentrations are different in these patients. I will use my laboratory to define what antibiotic concentrations we need to achieve and perform clinical studies with my collaborative network to demonstrate that we can redefine antibiotic dosing to reduce the emergence of superbugs ....>3000 Australians die every year from severe infections (nearly 3-fold higher in number than our annual road toll). These treatment failures are due to sub-optimal antibiotic dosing from a poor understanding of why concentrations are different in these patients. I will use my laboratory to define what antibiotic concentrations we need to achieve and perform clinical studies with my collaborative network to demonstrate that we can redefine antibiotic dosing to reduce the emergence of superbugs.Read moreRead less