Role Of Novel Mobile Elements In The Infiltration Of Antibiotic Resistance Genes Into Clinical Isolates.
Funder
National Health and Medical Research Council
Funding Amount
$421,650.00
Summary
Bacteria have a remarkable ability to capture and spread antibiotic resistance genes. This phenomenon is a particular problem in our hospitals and in the community as multi-drug resistant pathogenic organisms have been selected over time as a result of the use of antibitoics. Moreover the incidence of resistance appears to be on the increase. Once resistant strains appear they can greatly complicate the treatment of infections and the eradication of such pathogens from a hospital is both difficu ....Bacteria have a remarkable ability to capture and spread antibiotic resistance genes. This phenomenon is a particular problem in our hospitals and in the community as multi-drug resistant pathogenic organisms have been selected over time as a result of the use of antibitoics. Moreover the incidence of resistance appears to be on the increase. Once resistant strains appear they can greatly complicate the treatment of infections and the eradication of such pathogens from a hospital is both difficult and costly. We have been working on the problem of how antibiotic resistance genes are spread for a number of years and have identified a novel genetic element that can capture resistance genes by a process of site-specific recombination. This element, the integron, is common in mutli-drug resistant clinical isolates. To be captured by an integron, an antibiotic resistance gene has to be part of a mobile element known as a gene cassette. Although the application of antibiotics acts to amplify pathogens that are resistant and favours their persistance in hospitals, it is generally recognized that neither the gene cassette nor the drug resistance gene evolve in the hospital. Rather, these genes make their way into human pathogens from bacteria that normally reside in other environments, for example soil or water. In this project, we will investigate one route by which drug resistance genes and integrons might find their way into clinically relevant strains and what the sources of the resistance genes and gene cassettes might be. A greater understanding of these processes will help in developing strategies to limit the spread of drug resistant bacteria into and around hospitals.Read moreRead less
Molecular Genetics And Evolution Of Antibiotic Resistant Staphylococci
Funder
National Health and Medical Research Council
Funding Amount
$437,545.00
Summary
Potentially life-threatening 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. Hospital-acquired infections caused by Golden Staph are a major problem in Australia and globally. The problem is largely due to the pre ....Potentially life-threatening 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. Hospital-acquired infections caused by Golden Staph are a major problem in Australia and globally. The problem is largely due to the presence in hospitals of strains that have become resistant to most clinically-useful antibiotics and are therefore very difficult to eradicate. This research project will reveal detailed information about strains of Golden Staph that are currently prevalent in hospitals in Australia, USA, Europe, and South East Asia. It will also provide important insights into the mechanisms that enable this organism to become resistant so readily, and identify factors that promote the development of resistant strains. The results of this research project will lead to improved methods for the characterisation of clinical strains and the monitoring of antibiotic resistance. The findings will also be of relevance to other types of antibiotic resistant bacteria. Most importantly, the application of knowledge arising from these studies has potential to minimise the emergence of strains that are even more resistant, thereby extending the effectiveness of existing and future antibiotics. The design and implementation of strategies to limit the proliferation of resistant bacteria are essential if we are to avoid a scenario similar to that prior to the introduction of antibiotics, when serious infectious diseases were often untreatable.Read moreRead less
Plasmids are extra mini-chromosomes that are present in many bacteria. They carry information that enables their hosts to survive and prosper in hostile environments. Plasmids are able to spread rapidly between bacteria, ensuring that the information they carry is rapidly disseminated throughout bacterial populations. Many plasmids carry information that increases the virulence of their host bacteria, because it adds to their repertoire of toxins and other adjuncts to invasiveness and colonisati ....Plasmids are extra mini-chromosomes that are present in many bacteria. They carry information that enables their hosts to survive and prosper in hostile environments. Plasmids are able to spread rapidly between bacteria, ensuring that the information they carry is rapidly disseminated throughout bacterial populations. Many plasmids carry information that increases the virulence of their host bacteria, because it adds to their repertoire of toxins and other adjuncts to invasiveness and colonisation, or enables them to survive in the presence of antibiotics. The emergence of multi-drug resistant bacteria and the rapid spread of the ability of bacteria to withstand most antibiotics available to date were mediated by plasmids. Plasmids also carry information that ensures their own survival. The consequence of this is that their bacterial hosts retain the plasmids, even when it is no longer beneficial to do so. For example, plasmids carrying information for resistance to antibiotics are not lost when their bacterial hosts grow in the absence of antibiotics. This is because plasmids have control systems, which ensure that on the one hand, replication of the plasmid keeps pace with the replication of its host, and on the other hand that the plasmid does not produce so many copies of itself that it overwhelms its host. This project examines the intricate regulatory system that a group of antibiotic-resistance plasmids uses to ensure that on average each plasmid molecule is replicated once per bacterial cell cycle. This system uses an antisense RNA, a tertiary RNA structure (pseudoknot) that acts as a translational switch, and a protein that interacts with different sequences on the plasmid to initiate replication. Detailed knowledge of the processes underlying this complex system is required if we are to develop new treatments that will lead to elimination of antibiotic-resistance and virulence-contributing plasmids from populations of pathogenic bacteria.Read moreRead less
Plasmids are additional mini-chromosomes carried by many bacteria. They carry information that enables their hosts to prosper in otherwise hostile environments. Plasmids spread rapidly between bacteria, efficiently disseminating plasmid-borne information throughout bacterial populations. Many plasmids carry information that increases the virulence of their host. The emergence of multi-drug resistant bacteria and the rapid spread of the information enabling bacteria to withstand most antibiotics ....Plasmids are additional mini-chromosomes carried by many bacteria. They carry information that enables their hosts to prosper in otherwise hostile environments. Plasmids spread rapidly between bacteria, efficiently disseminating plasmid-borne information throughout bacterial populations. Many plasmids carry information that increases the virulence of their host. The emergence of multi-drug resistant bacteria and the rapid spread of the information enabling bacteria to withstand most antibiotics available today, were mediated by plasmids. Plasmids also carry information that ensures their own survival. Consequently, their hosts retain the plasmids even when it is no longer beneficial for them to do so. For example, plasmids mediating resistance to antibiotics are not lost when bacterial hosts are grown in the absence of those antibiotics. That is because plasmids have control systems, which ensure both that replication of the plasmid keeps pace with that of its host, and that the plasmid does not produce so many copies of itself that it overwhelms its host or places it at a competitive disadvantage amongst other bacteria. This project examines the intricate regulatory system that enables two groups of antibiotic-resistance plasmids to ensure that, on average, each plasmid molecule is replicated once per bacterial cell cycle. This system uses a tertiary RNA structure as a molecular switch, an antisense RNA as the regulator of this switch, and a protein that interacts with DNA sequences on the plasmid and with a bacterial protein, to initiate replication. Information gained from studies of plasmid systems is essential to the development of treatments for the elimination of antibiotic-resistance and virulence-contributing plasmids from populations of pathogenic bacteria. Antisense RNAs are not only a powerful research tool, but are also being developed for therapeutic use. Understanding how these RNAs interact with their targets will increase their effectiveness.Read moreRead less
Antibiotic resistance increases mortality and costs in the Intensive Care Unit (ICU), but the impact of antibiotic therapy has not been adequately studied. We propose to characterise the behaviour of key elements of the bacterial microflora (resistant bacteria and major resistance genes) in response to antibiotics. We have developed new rapid diagnostics to harness these data and this proposal has the potential to greatly improve diagnostic speed and accuracy and thus clinical outcomes.
The rapid emergence and spread of antibiotic resistance in bacteria that cause infectious diseases is of major concern to public health authorities throughout the world. Many of the genes that are responsible for this resistance are carried on mobile genetic elements, which are discrete segments of genetic material that can move from one bacterium to another. These genetic elements are important vehicles for the transmission of virulence and antibiotic resistance genes in most bacteria. This pro ....The rapid emergence and spread of antibiotic resistance in bacteria that cause infectious diseases is of major concern to public health authorities throughout the world. Many of the genes that are responsible for this resistance are carried on mobile genetic elements, which are discrete segments of genetic material that can move from one bacterium to another. These genetic elements are important vehicles for the transmission of virulence and antibiotic resistance genes in most bacteria. This project is centred on bacteria that cause intestinal diseases and have the potential to transfer genetic information to other bacteria that are present in the intestine. The focus will be on elucidating the mechanism of action of an enzyme encoded by two of these genetic elements. This enzyme is responsible for the movement of these elements from one site in the bacterial genome to another, by a process that is being increasingly recognised as important in antibiotic-resistant disease-causing bacteria. The project will employ the latest tools of molecular biology to determine the function of this enzyme, and its associated genetic elements, at the detailed molecular level. These studies will contribute to our understanding of how these antibiotic resistance elements are transferred within and between different bacterial cells. In the longer term the project will contribute towards the development of improved methods for the control and treatment of infectious diseases.Read moreRead less
QacA-mediated Multidrug Resistance And Export In Staphylococcus Aureus
Funder
National Health and Medical Research Council
Funding Amount
$497,250.00
Summary
Strains of the pathogenic bacterium Staphylococcus aureus (Golden Staph) which are resistant to almost all available anti-staphylococcal agents are responsible for serious infections among hospitalised 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 deter ....Strains of the pathogenic bacterium Staphylococcus aureus (Golden Staph) which are resistant to almost all available anti-staphylococcal agents are responsible for serious infections among hospitalised 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 for proteins which 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 which confer resistance by pumping a variety of structurally-dissimilar antimicrobials out of the bacterial cell. Proteins which recognise such a broad spectrum of compounds are called multidrug resistance 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 multidrug pumps are widespread in nature and are credited for resistance to antibiotics and other chemotherapeutic drugs in many pathogenic organisms, such as the bacteria responsible for tuberculosis, and in human cancer cells. In this project, we aim to characterise the QacA multidrug resistance protein which is involved in pumping many different antimicrobial compounds from staphylococcal cells. We will identify the regions of the QacA multidrug resistance 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 or block these drug resistance pumps, and will also provide fundamental knowledge applicable to the problem of multidrug resistance in other infectious diseases and cancer.Read moreRead less
QacA-mediated Multidrug Resistance And Export In Staphylococcus Aureus
Funder
National Health and Medical Research Council
Funding Amount
$437,545.00
Summary
Strains of the pathogenic bacterium Staphylococcus aureus (Golden Staph) which are resistant to almost all available anti-staphylococcal agents are responsible for serious infections among hospitalised 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 deter ....Strains of the pathogenic bacterium Staphylococcus aureus (Golden Staph) which are resistant to almost all available anti-staphylococcal agents are responsible for serious infections among hospitalised 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 for proteins which 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 which confer resistance by pumping a variety of structurally-dissimilar antimicrobials out of the bacterial cell. Proteins which recognise such a broad spectrum of compounds are called multidrug resistance 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 multidrug pumps are widespread in nature and are credited for resistance to antibiotics and other chemotherapeutic drugs in many pathogenic organisms, such as the bacteria responsible for tuberculosis, and in human cancer cells. In this project, we aim to characterise the QacA multidrug resistance protein which is involved in pumping many different antimicrobial compounds from staphylococcal cells. We will identify the regions of the QacA multidrug resistance 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 multidrug resistance in other infectious diseases and cancer.Read moreRead less
Multidrug Resistance Regulatory Protein QacR From Staphylococcus Aureus
Funder
National Health and Medical Research Council
Funding Amount
$459,750.00
Summary
One of the most significant mechanisms of drug resistance is the export of antibiotics and other chemotherapeutic drugs from the cell. Drug export systems are an important medical problem due to their frequent occurrence in bacteria and parasites which cause human disease, and in human cancer cells. Proteins which recognise and export a broad range of drugs from a cell are called multidrug efflux pumps. These multidrug efflux systems present a serious threat to patient care and to successful the ....One of the most significant mechanisms of drug resistance is the export of antibiotics and other chemotherapeutic drugs from the cell. Drug export systems are an important medical problem due to their frequent occurrence in bacteria and parasites which cause human disease, and in human cancer cells. Proteins which recognise and export a broad range of drugs from a cell are called multidrug efflux pumps. These multidrug efflux systems present a serious threat to patient care and to successful therapy, since the ability to produce a single protein simultaneously renders the cell or organism resistant to several different drugs. Strains of the bacterial pathogen Staphylococcus aureus or Golden Staph, which are endemic in hospitals world-wide, contain an example of such a multidrug exporter, the QacA multidrug efflux pump. QacA exports at least 30 different antimicrobial compounds, including antiseptics and disinfectants. Production of this protein is regulated by a sensor protein, QacR, which detects the presence of a number of these antimicrobial compounds. To understand how the QacR sensor protein can recognise such a wide variety of compounds, we will identify and structurally characterise the regions of the QacR multidrug regulatory protein which bind these compounds. Additionally, we will examine the means by which QacR regulates the production of the QacA pump protein. This project will provide fundamental knowledge that will not only help with understanding the important process of multidrug resistance but will also enable the rational design of more effective antibacterial compounds that either block or evade these multidrug efflux systems.Read moreRead less
Multidrug Resistance Regulatory Protein QacR From Staphylococcus Aureus
Funder
National Health and Medical Research Council
Funding Amount
$196,527.00
Summary
One of the most significant mechanisms of drug resistance is the export of antibiotics and other chemotherapeutic drugs from the cell. Drug export systems are an important medical problem due to their frequent occurrence in bacteria and parasites which cause human disease and in human cancer cells. Proteins which recognise and export a broad range of drugs from a cell are called multidrug efflux pumps. These multidrug efflux systems present a serious threat to patient care and to successful ther ....One of the most significant mechanisms of drug resistance is the export of antibiotics and other chemotherapeutic drugs from the cell. Drug export systems are an important medical problem due to their frequent occurrence in bacteria and parasites which cause human disease and in human cancer cells. Proteins which recognise and export a broad range of drugs from a cell are called multidrug efflux pumps. These multidrug efflux systems present a serious threat to patient care and to successful therapy, since the ability to produce a single protein simultaneously renders the cell or organism resistant to several different drugs. Strains of the bacterial pathogen Staphylococcus aureus or Golden Staph, which are endemic in hospitals world-wide, contain an example of such a multidrug exporter, the QacA multidrug efflux pump, which exports at least 30 different antimicrobial compounds, including antiseptics and disinfectants. Production of this protein is regulated by a sensor protein, QacR, which detects the presence of a number of these antimicrobial compounds. To understand how the QacR sensor protein can recognise such a wide variety of compounds, we will identify and structurally characterise the regions of the QacR multidrug regulatory protein which bind these compounds. Additionally, we will examine the means by which QacR regulates the production of the QacA pump protein. This project will provide fundamental knowledge that will not only help with understanding the important process of multidrug resistance but will also enable the rational design of more effective antibacterial compounds that either block or evade these multidrug efflux systems.Read moreRead less