A New Class Of Inhibitors For The Treatment Of Tuberculosis
Funder
National Health and Medical Research Council
Funding Amount
$720,691.00
Summary
Tuberculosis (TB) remains a major cause of mortality and morbidity worldwide, with 1.3 million deaths annually. Some strains of the TB bacterium are resistant to all available drugs. We have identified novel chemical structures that display potent and specific activity against pathogenic mycobacteria. In this proposal we will develop optimised derivatives with more potent activity against mycobacteria, assess their stability and toxicity and determine their mode of action.
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.
Reversing Antibiotic Resistance With Efflux Pump Inhibitors
Funder
National Health and Medical Research Council
Funding Amount
$494,174.00
Summary
Antibiotic resistance in dangerous pathogens is one of the greatest threats to human health of the 21st century. The main cause of multidrug resistance is the presence of drug efflux pumps, which remove antibiotics from the bacterial cell thereby lowering the antibiotic concentration inside the cells to sub-toxic levels. We will use our expertise on these efflux pumps and on how to inhibit them to develop compounds that could reverse resistance and restore the activity of antibiotics.
Design, Development And Analysis Of New Tuberculosis Drugs
Funder
National Health and Medical Research Council
Funding Amount
$736,628.00
Summary
Serious issues of drug resistance have emerged in tuberculosis prevention and are placing enormous pressure on global health systems. We have identified an enzyme of M. tuberculosis that is essential for its survival. This project will develop potent inhibitory compounds for this enzyme. Further, we will identify new drug targets through a screen to specifically identify the genes of the organism essential for its survival in the body. This information will be used to develop new TB drugs.
Exploitation Of Bacterial Transcription Initiation As A Target For New Antimicrobials
Funder
National Health and Medical Research Council
Funding Amount
$540,356.00
Summary
Antibiotic resistant infections from 'superbugs' are a major health problem. We will exploit information we have gathered on the machinery that copies genetic information into a message to discover chemical compounds that can be used for the development of new antibiotics with a novel mechanism of action.
Determining The Bacterial Contributions To Tuberculosis And Identification Of Drug Targets
Funder
National Health and Medical Research Council
Funding Amount
$443,946.00
Summary
Serious issues of drug resistance have emerged in tuberculosis prevention and are placing enormous pressure on global health systems. We have identified an enzyme of M. tuberculosis that is essential for its survival. This project will develop potent inhibitory compounds for this enzyme. Further, we will identify new drug targets through a screen to specifically identify the genes of the organism essential for its survival in the body. This information will be used to develop new TB drugs.
Once treatable infections are becoming deadly because bacteria are developing broad antibiotic resistance. New medicines are urgently needed. Microbes themselves are the richest known source of new antibiotics but finding the 'good bugs' is like finding a needle in a microbial haystack. This project will use state-of-the art science to screen a previously overlooked source of rich microbial biodiversity and find new antibiotics.
Developing New Therapies To Combat Tuberculosis Through Inhibition Of Vitamin B5 Metabolism In The Organism That Causes The Disease
Funder
National Health and Medical Research Council
Funding Amount
$311,760.00
Summary
The metabolism of vitamin B5 by pathogenic microorganisms has been recognised as an attractive target for developing drugs to combat various infectious diseases. The aim of the proposed work is to develop inhibitors of vitamin B5 metabolism in the bacterium that causes tuberculosis, using a powerful, multidisciplinary approach known as “fragment-based drug discovery”. This work is likely to yield potent inhibitors of the target bacterium, which could ultimately be used to treat tuberculosis.
Molecular Epidemiology Of Mycobacterium Tuberculosis Infection In The Northern Territory, Australia
Funder
National Health and Medical Research Council
Funding Amount
$122,714.00
Summary
The Northern Territory (NT) of Australia has the highest jurisdiction-specific rates of tuberculosis (TB) in Australia, and TB is a disease that disproportionately affects Indigenous people. The factors that contribute to the spread of TB in the NT are incompletely understood. We plan to use technology known as “whole genome sequencing” of bacterial DNA to better the understanding of the spread of TB in the NT. This will help guide TB control policies.
Efflux Mediated Multidrug Resistance In Staphylococcus Aureus
Funder
National Health and Medical Research Council
Funding Amount
$738,056.00
Summary
Strains of the pathogenic bacterium Staphylococcus aureus (Golden Staph), resistant to almost all available anti-staphylococcal agents, are responsible for serious infections among patients; in some hospitals such outbreaks reach epidemic proportions. In these bacteria, resistance has emerged to all classes of antimicrobial agents, including antibiotics and antiseptics-disinfectants commonly used in the hospital environment, largely due to the acquisition of resistance determinants. These determ ....Strains of the pathogenic bacterium Staphylococcus aureus (Golden Staph), resistant to almost all available anti-staphylococcal agents, are responsible for serious infections among patients; in some hospitals such outbreaks reach epidemic proportions. In these bacteria, resistance has emerged to all classes of antimicrobial agents, including antibiotics and antiseptics-disinfectants commonly used in the hospital environment, largely due to the acquisition of resistance determinants. These determinants encode proteins that provide the bacterial cell with a range of different biochemical mechanisms to evade antibiotic chemotherapy. Specifically, this project seeks to increase our understanding of proteins that confer resistance by pumping structurally-dissimilar antimicrobials out of the cell. The importance of these proteins in the biology of organisms is implied by the fact that an overwhelming majority of the drug targets are membrane proteins. Proteins which recognise such a broad spectrum of compounds are called multidrug resistance (MDR) proteins and present a disturbing clinical threat since the acquisition of one such system by a cell may simultaneously decrease its susceptibility to a number of antimicrobials. Similar MDR pumps are widespread in nature and are credited for resistance to antibiotics and other chemotherapeutic drugs in many pathogenic organisms and in human cancer cells. In this project, we aim to characterise the QacA MDR protein which is involved in pumping many different antimicrobial compounds from staphylococcal cells. We will identify the regions of the QacA MDR protein which bind the compounds and examine how the protein expels them to give resistance. These studies are a prerequisite for the design of more effective antibacterial compounds able to bypass these drug resistance pumps and will also provide fundamental knowledge applicable to the problem of MDR in other infectious diseases and cancer.Read moreRead less