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
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