Modelling Streptococcal Urogenital Tract Infection To Study Mechanisms Of Bacterial Colonization And Persistence
Funder
National Health and Medical Research Council
Funding Amount
$412,085.00
Summary
Colonization of the urogenital tract with bacterial pathogens is one of the most common infections in humans. In Australia millions of people are colonized in their urogenital tracts at any given time, often asymptomatically, and many such individuals require medical intervention for the treatment of consequent infections that result from persistent colonization. Bacterial colonization of the urogenital tract is associated with a variety of disease presentations including urinary tract infection ....Colonization of the urogenital tract with bacterial pathogens is one of the most common infections in humans. In Australia millions of people are colonized in their urogenital tracts at any given time, often asymptomatically, and many such individuals require medical intervention for the treatment of consequent infections that result from persistent colonization. Bacterial colonization of the urogenital tract is associated with a variety of disease presentations including urinary tract infections and neonatal infections resulting from vertical transmission of colonizing bacteria from mothers to newborns. Aside from sexually-transmitted diseases the most prominent bacterial pathogens that colonize the urogenital tract are Group B Streptococcus (GBS) and Escherichia coli. GBS in particular exist in the female urogenital tract as a persistent microbial reservoir in up to 40% of pregnant women and are transmitted to newborns in up to 72% of live births. Colonization of newborns leads to invasive disease including pneumonia, sepsis, and meningitis. While the disease presentations resulting from colonization of the urogenital tract vary the underlying basis that leads to disease is antecedent bacterial persistence in the urogenital tract despite immune system activation. The mechanisms whereby GBS evade immune responses in the urogenital tract to allow their survival are unknown. I will define the immune-evasion mechanisms and virulence traits used by GBS, as a model urogenital pathogen, to successfully colonize the urogenital tract in the face of mounting immune responses. These studies will provide a better understanding of the pathogenesis of urogenital disease in terms of bacterial colonization and immune-evasion strategies. This will shed light onto new approaches for the prevention and treatment of urogenital disease in humans such as improved vaccination, locally acting cytokines, and deliberate colonization with non-invasive strains for the prevention of disease.Read moreRead less
False Positives In The Diagnosis Of Sexually Transmitted Chlamydia Trachomatis Infection In Children
Funder
National Health and Medical Research Council
Funding Amount
$724,313.00
Summary
Chlamydia trachomatis causes sexually transmitted infections, and also the eye disease trachoma. The detection of Chlamydia in urine sample from a child can be seen as evidence for sexual abuse. We will assess the potential impacts of three mechanisms that could conceivably lead to urogenital Chlamydia diagnosis in a child in the absence of sexual abuse: contamination of the urogenital site with ocula Chlamydia, contamination of urine samples after collection, and diagnostic test malfunction.
Molecular Mechanisms Of Plasmid Maintenance In Multiply-resistant Staphylococci
Funder
National Health and Medical Research Council
Funding Amount
$543,778.00
Summary
Serious infections caused by Staphylococcus aureus bacteria, commonly known as Golden Staph, often arise as complications in patients within hospitals. These infections compromise the health of the patient and jeopardise their recovery from the condition for which they were initially admitted, which significantly increases healthcare costs. Golden Staph is a major cause of hospital-acquired infections in Australia and globally. The problem is largely due to the presence in hospitals of strains t ....Serious infections caused by Staphylococcus aureus bacteria, commonly known as Golden Staph, often arise as complications in patients within hospitals. These infections compromise the health of the patient and jeopardise their recovery from the condition for which they were initially admitted, which significantly increases healthcare costs. Golden Staph is a major cause of hospital-acquired infections in Australia and globally. The problem is largely due to the presence in hospitals of strains that are resistant to most clinically-useful antibiotics and are therefore very difficult to eradicate; the recent isolation of strains highly-resistant to one of the last resort anti-staphylococcal antibiotics, vancomycin, is particularly worrying, as is the emergence of resistant strains that cause infections in the wider community. The emergence of these multiresistant strains is primarily attributable to the acquisition of pre-existing resistance determinants by cell-to-cell gene transfer, a process in which plasmids, extra-chromosomal DNA elements, play a prominent role. Staphylococcal multiresistance plasmids carry genes that can confer resistance to up to 20 antimicrobial agents and are themselves capable of transfer between bacterial cells. In this project, we will define the molecular mechanisms by which multiresistance plasmids efficiently replicate in the host cell and are stably maintained in bacterial populations. This information will identify targets for agents that can promote the loss of plasmids and hence combat the development of resistance; the activity of one type of agent will be determined in this project. The application of knowledge arising from these studies to has the potential to extend the efficacy of existing and future antimicrobial therapies.Read moreRead less
The Pathogenesis Of Infections Caused By Clostridium Sordellii.
Funder
National Health and Medical Research Council
Funding Amount
$400,232.00
Summary
The bacterium Clostridium sordellii causes necrosis and multiorgan failure with a very high mortality rate of 70% in infections of drug users, transplant and post-abortion patients, and 100% for post-partum patients. Little is known about how C. sordellii causes such devastating disease; treatment of these infections is currently ineffective. This project will make a major contribution to our understanding of how disease is caused and may lead to improved prevention and treatment stratetegies.
Zinc: The Molecular Basis Of It�s Toxicity To Gram-positive Pathogens And It�s Exploitation By The Innate Immune Response
Funder
National Health and Medical Research Council
Funding Amount
$588,398.00
Summary
Zinc in excess is toxic to bacteria, and the release of zinc is an important part of the immune response. Dietary zinc deficiency leads to increased susceptibility to pathogenic bacteria. How zinc affords protection has remained a mystery. We have identified a novel mechanism in 2 priority human pathogens by which zinc competes for the essential metal ion manganese. We will elucidate the molecular details of this mechanism and how it is harnessed by the immune system.
Molecular Mechanisms Of Low-level Vancomycin Resistance In Clinical Staphylococcus Aureus
Funder
National Health and Medical Research Council
Funding Amount
$437,916.00
Summary
The common bacteria Staphylococcus aureus causes many infections in humans, and is becoming more resistant to antibiotic treatments, especially in hospitals. This project will determine how this bacteria is developing resistance to some of our last available antibiotics. This will provide an important basis for detecting and preventing this antibiotic resistance problem in future.
A remarkable feature of bacterial cells though is that they can share genes. In so doing bacteria have the ability to acquire completely new characteristics. One example of this spreading of genes is the rapid dissemination of antibiotic resistance in pathogenic bacteria and the creation of multi-resistant superbugs. This process contributes greatly to the problem of hospiatal acquired infeections and results in many patient deaths annually. The other aspect of this sharing of genes is that in a ....A remarkable feature of bacterial cells though is that they can share genes. In so doing bacteria have the ability to acquire completely new characteristics. One example of this spreading of genes is the rapid dissemination of antibiotic resistance in pathogenic bacteria and the creation of multi-resistant superbugs. This process contributes greatly to the problem of hospiatal acquired infeections and results in many patient deaths annually. The other aspect of this sharing of genes is that in a population some cells will lack genes that others have. Some of these shared genes apart from antibiotic resistance can be a concern and include traits that make some bacteria pathogenic. Thus, two cells of the same species may have very different abilities to cause disease based on what additional genes they carry. Genomics is becoming one of the great scientific revolutions of the 21st century. Over 160 microbial genomes have been sequenced to date and from these studies we have also learned many important things including how some bacteria cause disease. Mobile DNA presents unique challenges to microbial genomics however since different individuals in a species can have many different genes. Thus genomics on even many individuals of a species may miss bacterial genes important to us. Here we will be applying genomics in a way that specifically targets those genes that are shared. This will have many benefits. We will be able to greatly increase our rate of discovery of medically important and other genes in way that is targeted. This approach will allow us to discover these shared genes in a way that is much more cost effective and faster than conventional whole cell genomics. It will also allow us to gain an understanding of how benign bacteria associated with humans may act as reservoirs for passing on harmful genes to bacteria that cause hospital infections.Read moreRead less
A Novel CD39-like Ecto-NTPDase Of Legionella Pneumophila
Funder
National Health and Medical Research Council
Funding Amount
$362,046.00
Summary
Legionnaire's disease is a serious cause of community acquired pneumonia. We are studying the way the Legionella bacteria persist in the environment and cause disease. We have found that Legionella produces a specific protein that mimics the action of a human protein. This proposal aims to work out how the bacteria use this protein to infect the human lung and escape killing by immune cells. The results from this study will help to determine if this protein may be used as a target for the develo ....Legionnaire's disease is a serious cause of community acquired pneumonia. We are studying the way the Legionella bacteria persist in the environment and cause disease. We have found that Legionella produces a specific protein that mimics the action of a human protein. This proposal aims to work out how the bacteria use this protein to infect the human lung and escape killing by immune cells. The results from this study will help to determine if this protein may be used as a target for the development of new anti-infective drugs.Read moreRead less
Uropathogenic Escherichia coli (UPEC) are a major cause of urinary tract infections (UTI) and sepsis. Recently, a highly virulent clone of UPEC (E. coli ST131) that is resistant to multiple types of antibiotics has emerged worldwide. This project addresses the mechanisms by which E. coli ST131 can colonise the urinary tract and cause disease. The outcomes of this project will be a better understanding of how E. coli ST131 causes disease, and potentially new treatment regimes for UTI.
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