Potent Antibiotics Against Drug-resistant Tuberculosis
Funder
National Health and Medical Research Council
Funding Amount
$531,410.00
Summary
Tuberculosis (TB) is a significant killer and caused 1.7 million deaths in 2009. The disease affects all countries, including Australia, in which the incidence in the indigenous population is 14 times higher than that in the non-indigenous population. We will develop a new anti-TB drug that can replace or enhance the current drugs that are not effective against drug resistant TB.
Interaction Of New Kinase Inhibitor Drugs With Multi-drug Resistance (MDR) Transporter Proteins.
Funder
National Health and Medical Research Council
Funding Amount
$411,000.00
Summary
Multidrug transporter proteins are remarkable molecular pumps that expel a wide variety of drugs and toxins from cells. They are located at strategic sites where they eliminate harmful substances from the body or prevent them being absorbed from our diet in the first place. Multidrug transporters are also found at natural barriers within the body where they protect vulnerable tissue compartments, including the brain, cerebrospinal fluid, testes and, in preganant women, the foetus. Nevertheless, ....Multidrug transporter proteins are remarkable molecular pumps that expel a wide variety of drugs and toxins from cells. They are located at strategic sites where they eliminate harmful substances from the body or prevent them being absorbed from our diet in the first place. Multidrug transporters are also found at natural barriers within the body where they protect vulnerable tissue compartments, including the brain, cerebrospinal fluid, testes and, in preganant women, the foetus. Nevertheless, multidrug transporters sometimes interfere with drug therapy. They can prevent efficient absorption of drugs, increase the rate of drug elimination from the body, or prevent drug access to some tissues . Moreover, the activity of the transporters is quite variable, both between patients and within the same patient over time. This makes it difficult to provide optimal drug doses, particularly when treating cancer, where the drugs must be given at the maximum tolerated dose. The presence of drug transporter proteins in tumour cells can prevent entry of anticancer drugs, rendering them resistant to treatment. This is the main cause of failure in chemotherapy. This project will investigate a class of very promising new anticancer drugs, kinase inhibitors, to determine whether they are pumped by multidrug transporters, whether they alter the amounts of drug transporters in cells, and whether they alter transporter activity. We will also determine the consequences that follow from this for drug therapy. This information will help clinicians to rationally optimise therapy with the new drugs, to identify in advance both favourable (synergistic) and unfavourable (harmful) drug interactions in combination chemotherapy, to optimise drug doses and to minimise toxic side effects. The information will also add to our general understanding of drug absorption and elimination, and to the basic science of the remarkable multidrug transporter proteins.Read moreRead less
Plasmodium Knowlesi As A Genetic Model For Plasmodium Vivax Drug Resistance
Funder
National Health and Medical Research Council
Funding Amount
$417,193.00
Summary
Two different Plasmodium parasites cause the majority of malaria worldwide. However, one type, P. vivax, is unable to be cultured in the laboratory and therefore has been poorly studied. Drug resistance has been observed but the underlying causes are poorly understood. We propose to use a closely related parasite, P. knowlesi, as a model to understand drug resistance mechanisms. This knowledge will be used to follow resistance in the field and direct policy of the most appropriate treatment.
Novel Membrane-targeted Antibiotics Against Drug-resistant Gram-positive Bacterial Infections
Funder
National Health and Medical Research Council
Funding Amount
$1,351,496.00
Summary
This project aims to develop a best in class antibiotic, Vancapticin, with superior efficacy, broader spectra of action and improved therapeutic index than existing therapies for Gram-positive (G+ve) bacterial infections. The research team has identified lead candidates that offer equivalent &/or superior potency, efficacy & pharmacokinetic profiles compared to several clinical comparators. NHMRC Development funding is required to select a candidate for an Investigative New Drug application.
Structure-based Design Of Novel Therapeutics For Multi-drug Resistant Neisseria Gonorrhoeae
Funder
National Health and Medical Research Council
Funding Amount
$669,148.00
Summary
Multiple drug resistance (MDR) in bacteria represents one of the most intractable problems facing modern medicine. The recent superbug, MDR-Neisseria gonorrhoeae (MDR-Ng), causes the sexually transmitted infection gonorrhoeae. A multi disciplinary team with expertise in structural biology, medicinal chemistry and bacteriology will establish a comprehensive knowledge base aimed at developing new antibiotics to treat MDR-Ng by targeting a bacterial protein virulence factor.
An Ace Up Their Sleeve: Characterisation Of A Novel Family Of Drug Efflux Systems Represented By The Acinetobacter AceI Exporter
Funder
National Health and Medical Research Council
Funding Amount
$400,286.00
Summary
Chlorhexidine is widely used as an antiseptic in products such as skin washes, soaps, mouthwashes, disinfectants and preservatives. We have recently discovered a novel bacterial protein which pumps chlorhexidine out of bacterial cells to make them resistant to this antiseptic agent. This proposal aims to understand this resistance mechanism and to find inhibitors which could be applied in clinical settings to augment the activity of chlorhexidine.
Non-Haemolytic Friulimicins For The Treatment Of Multi-Drug Resistant Bacteria
Funder
National Health and Medical Research Council
Funding Amount
$552,572.00
Summary
We are developing a new antibiotic, called friulimicin, to combat the ïsuperbugsÍ that cause serious infections in hospitals and the community. We will optimize the drug to target MRSA (methicillin resistant Staphylococcus aureus) VRE (vancomycin resistant enterococci) and DRSP (drug resistant Streptococcus pneumoniae). We will also investigate how the drug can be used for treatment of lung infections such as pneumonia, where the antibiotic can work much better than existing drugs against resist ....We are developing a new antibiotic, called friulimicin, to combat the ïsuperbugsÍ that cause serious infections in hospitals and the community. We will optimize the drug to target MRSA (methicillin resistant Staphylococcus aureus) VRE (vancomycin resistant enterococci) and DRSP (drug resistant Streptococcus pneumoniae). We will also investigate how the drug can be used for treatment of lung infections such as pneumonia, where the antibiotic can work much better than existing drugs against resistant bacteria.Read moreRead less
Developing Synergisers Of The Antimalarial Drug, Chloroquine, For The Treatment Of Chloroquine-resistant P. Falciparum.
Funder
National Health and Medical Research Council
Funding Amount
$243,000.00
Summary
Malaria is a debilitating parasitic disease that is responsible for the deaths of about two million children each year. As drugs, such as chloroquine, become increasingly useless due to the development of parasite resistance, there is an urgent need to understand the mode of action of and the molecular basis of resistance to existing antimalarials and to design affordable treatments that can replace chloroquine. It is known that some compounds, that have only poor antimalarial activity themselve ....Malaria is a debilitating parasitic disease that is responsible for the deaths of about two million children each year. As drugs, such as chloroquine, become increasingly useless due to the development of parasite resistance, there is an urgent need to understand the mode of action of and the molecular basis of resistance to existing antimalarials and to design affordable treatments that can replace chloroquine. It is known that some compounds, that have only poor antimalarial activity themselves, can synergise the action of chloroquine. This may involve the inhibition of the activity of proteins that directly or indirectly extrude chloroquine from its site of action in the parasite's digestive apparatus. Unfortunately, thechloroquine synergisers examined to date have been too toxic to be useful in vivo. In preliminary studies we have identified some compounds that would be suitable for use in malaria patients, including a widely used antimalarial drug, primaquine, that can synergise the activity of chloroquine against chloroquine-resistant parasites. We will attempt to understand the molecular basis of this interaction. This will allow us to define optimal combinations of chloroquine and a resistance-reversing quinoline for use treating malaria. This could extend the clinical life of this important antimalarial drug. The information obtained may also help to design novel antimalarial drugs.Read moreRead less
The PH Of The Malaria Parasite's Digestive Vacuole And Its Role In Antimalarial Drug Resistance
Funder
National Health and Medical Research Council
Funding Amount
$210,990.00
Summary
Malaria is an infectious disease that infects an estimated 300-500 million people and kills an estimated 1.5-2.7 million people annually. The microscopic parasite responsible for the disease is becoming increasingly resistant to most of the antimalarial drugs presently available. However the mechanisms by which it does so are very poorly understood. The malaria parasite invades the red blood cells of its victim. Once itside, it sets about consuming the contents of the cell, ingesting them and de ....Malaria is an infectious disease that infects an estimated 300-500 million people and kills an estimated 1.5-2.7 million people annually. The microscopic parasite responsible for the disease is becoming increasingly resistant to most of the antimalarial drugs presently available. However the mechanisms by which it does so are very poorly understood. The malaria parasite invades the red blood cells of its victim. Once itside, it sets about consuming the contents of the cell, ingesting them and depositing them in a small acidic compartment called the digestive vacuole. Many of the antimalarial drugs presently in use target this compartment and interfere with the processes going on inside it. There is evidence that resistance to antimalarial drugs arises as a result of changes in this compartment, though what these changes are, and how they occur remains a mystery. This work focuses on the mechanisms involved in controlling the acidity of the parasite's digestive vacuole. We have preliminary evidence that parasites showing different levels of antimalarial drug resistance have different levels of acidity in their vacuoles, and that this may be due to differences in the rate at which acid leaks from this compartment. The aim of this work is to obtain a detailed understanding on the mechanisms by which the acidity of the parasite's digestive vacuole is regulated and to gain some insight into whether and how these mechanisms might differ between drug-resistant and drug-sensitive parasites. By so doing, this work might be expected, in the long term, to provide a basis for the devolpment of new drugs with which to combat this deadly and increasingly threatening disease.Read moreRead less
Development Of Novel Hybrid Antibiotics For The Treatment Of Hospital And Community Acquired Drug Resistant Gram-Negative And Gram-Postitive Bacterial Infections
Funder
National Health and Medical Research Council
Funding Amount
$715,076.00
Summary
Drug resistant bacteria now pose a serious and growing threat to human health. Many bacteria have developed new resistance mechanisms such that most common antibiotics no longer can protect patients from serious, life-threatening infection. We will modify two existing antibiotics, colistin and carbapenem (a penicillin), to convert it into a more powerful antibiotic that targets resistant bacteria.