Identification And Analysis Of Novel Replication Initiation Factors In Staphylococcus Aureus
Funder
National Health and Medical Research Council
Funding Amount
$311,789.00
Summary
Multi-drug resistant Golden staph is a serious medical problem around the world because strains are often resistant to commonly used treatments; new drugs are therefore urgently required. DNA replication is a fundamental process that is essential for the survival of all cellular organisms. This project aims to identify and characterise novel factors involved in DNA replication in Golden staph, which represent potential drug targets.
Molecular Characterization Of The Role Of FtsK In Chromosome Unlinking And Segregation.
Funder
National Health and Medical Research Council
Funding Amount
$471,022.00
Summary
Bacterial pathogens, especially those associated with multiple drug resistances, are becoming increasingly serious health problems. This project will investigate the key protein FtsK and the role it plays in co-ordinating bacterial chromosome segregation and cell division. FtsK from three specific pathogens, Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus, will be characterized to better understand its vital role, and to inform and focus future drug design.
Nucleic Acid Synthesis And Cell Division In Model Pathogenic Bacteria
Funder
National Health and Medical Research Council
Funding Amount
$781,345.00
Summary
The rise of antibiotic resistance, particularly in hospitals, over recent years represents a huge financial burden on the health system, in addition to the personal costs to the patient infected. Over the last 60 years, we have become accustomed to the availability of antibiotics that can effectively treat most, if not all, bacterial infections. Today, this is not the case, and some bacteria in hospitals are resistant to all therapeutically useful antibiotics. The costs of drug development are v ....The rise of antibiotic resistance, particularly in hospitals, over recent years represents a huge financial burden on the health system, in addition to the personal costs to the patient infected. Over the last 60 years, we have become accustomed to the availability of antibiotics that can effectively treat most, if not all, bacterial infections. Today, this is not the case, and some bacteria in hospitals are resistant to all therapeutically useful antibiotics. The costs of drug development are very considerable; from the financial perspective of a pharmaceutical company, the de novo development of new antibiotics is not attractive because they are drugs that are only used for a short period. Recoupment of development costs takes a long time. As a result, very few new antibiotics are currently in development, and many of the newer ones are the result of academic efforts and subsequent formation of spin-out companies that develop new drugs through to phase 1 trials. The need for new, and effective, antibiotic therapies is pressing. We propose to identify and validate the use of key essential biological processes as targets for the development of new antimicrobial agents in two important hospital pathogens. Staphylococcus aureus is a well known and established pathogen that is the number one cause of hospital acquired (nosocomial) infections. Acinetobacter sp. is a relatively new problem in nosocomial infections, but is growing in importance due to the startling rate at which it is able to acquire resistance to antibiotics. In both organisms, we intend to target essential protein-protein interactions involved in DNA replication (duplication of genetic material), transcription (production of a genetic message), and cell division. The targeting of protein-protein interactions, rather than the enzymic activity of a protein provides a novel and unexploited avenue for antibacterial development with great potential for success.Read moreRead less
Some of the world's most important diseases, including important diseases of indigenous chilren and the hospitalised elderly are caused by bacteria that carry a surface coating called a capsule. It is not clear how this capsule is retained by bacteria. Resolution of this question could lead to the development of new disinfectants that will stop hospital-acquired infections, to new reagents that can be incoporated into medical devices where bacteria frequently grow, and new antibiotics.
Molecular Basis Of O-antigen Modification And Genomics Of Serotype-converting Bacteriophages Of Shigella Flexneri
Funder
National Health and Medical Research Council
Funding Amount
$268,264.00
Summary
There are approximately 165 million cases of shigellosis world wide annually, resulting in 1.1 million deaths. The majority of cases occur in developing countries and most deaths occur in children under 5 years of age. Shigellosis is mainly caused by the bacterium Shigella flexneri. There are 13 different serotypes of S. flexneri determined by bacterial cell-surface polysaccharides called O-antigens. Bacterial viruses (bacteriophages) carry the genes which confer O-antigen variation. Infection a ....There are approximately 165 million cases of shigellosis world wide annually, resulting in 1.1 million deaths. The majority of cases occur in developing countries and most deaths occur in children under 5 years of age. Shigellosis is mainly caused by the bacterium Shigella flexneri. There are 13 different serotypes of S. flexneri determined by bacterial cell-surface polysaccharides called O-antigens. Bacterial viruses (bacteriophages) carry the genes which confer O-antigen variation. Infection and subsequent incorporation of the virus into the genetic material of the bacterial cell result in modification of the bacterial O-antigen. This phage-mediated O-antigen modification gives rise to different serotypes. The project will address fundamental processes related to the O-antigen modification. This will be achieved by studying structure and function of the enzymes encoded by the O-antigen modification gene cluster. We have isolated several serotype-converting bacteriophages from S. flexneri and we plan to compare and characterise their genomic information to increase understanding of their origin and relationship with the bacterial host.Read moreRead less
Urinary tract infections (UTI) are among the most common infectious diseases of humans and a major cause of morbidity and mortality. In the USA, UTI accounts for >$1.6 billion in medical expenses each year. It is estimated that 50% of women will develop a UTI in their lifetime. This research aims to understand the processes by which bacteria colonize the human bladder. The work has implications for the development of new approaches to prevent and treat UTI.
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
The Team brings together a unique grouping of people with backgrounds in molecular biology, medical microbiology, microbiology, marine ecology and immunology to tackle a significant health problem infections caused by bacteria. Using a novel approach, based on understanding how marine organisms specifically interfere with bacterial colonisation, the Team over the past seven years has identified a group of compounds that represent a novel group of antibiotics. Publications and patenting by the Te ....The Team brings together a unique grouping of people with backgrounds in molecular biology, medical microbiology, microbiology, marine ecology and immunology to tackle a significant health problem infections caused by bacteria. Using a novel approach, based on understanding how marine organisms specifically interfere with bacterial colonisation, the Team over the past seven years has identified a group of compounds that represent a novel group of antibiotics. Publications and patenting by the Team has demonstrated that the Team is at the forefront of research in this area. The novel antibiotics work by preventing bacteria sticking to surfaces and by preventing the bacteria from releasing toxins. The studies will concentrate on those bacteria that produce infections in the lungs (acute pneumonia), eyes (corneal infection), ear (middle ear disease), and abscesses.Read moreRead less
Identifying The Physiological Conditions That Promote Lateral Gene Transfer And Evolution Of New Streptococcal Pathovars
Funder
National Health and Medical Research Council
Funding Amount
$415,907.00
Summary
In the last few decades, the diseases caused by the three human pathogens, groups A, B and G streptococcus have undergone a transformation. The exchange of DNA between these species is speculated to play a role in this changing disease association. In this proposal we will identify the specific physiological and growth conditions that promote DNA transfer. Such information may help in our understanding of how new pathogenic strains of streptococci arise.