Inhibitors of enzymes in the lysine biosynthetic pathway. Recent reports of increasing bacterial resistance to antibiotics highlight the need for continual development of new antibacterial agents. Inhibitors of the biosynthesis of the amino acid lysine - an essential component of bacterial proteins and cell wall - may provide a novel class of antibiotics. This project describes investigations of the mechanism of the first two enzymes in the lysine biosynthetic pathway and the design and synthesi ....Inhibitors of enzymes in the lysine biosynthetic pathway. Recent reports of increasing bacterial resistance to antibiotics highlight the need for continual development of new antibacterial agents. Inhibitors of the biosynthesis of the amino acid lysine - an essential component of bacterial proteins and cell wall - may provide a novel class of antibiotics. This project describes investigations of the mechanism of the first two enzymes in the lysine biosynthetic pathway and the design and synthesis of inhibitors of these enzymes.Read moreRead less
Novel peptide mimics for the disruption of chemical communication in bacteria. It is now well established that bacteria communicate with each other via small diffusible signalling molecules and coordinate their activities such as biofilm formation, swarming and expression of virulence factors in a coordinated manner. This project will investigate the synthesis of novel organic molecules that have the capacity to disrupt chemical communication in bacteria. This could allow control of the unwante ....Novel peptide mimics for the disruption of chemical communication in bacteria. It is now well established that bacteria communicate with each other via small diffusible signalling molecules and coordinate their activities such as biofilm formation, swarming and expression of virulence factors in a coordinated manner. This project will investigate the synthesis of novel organic molecules that have the capacity to disrupt chemical communication in bacteria. This could allow control of the unwanted microbial activity without the use of growth inhibitory agents such as antibiotics, preservatives and disinfectants that select for the resistant organisms. This elegant approach to eradicating the virulence behaviour of microbes represents a novel strategy to combat antimicrobial resistance.Read moreRead less
New scaffolds for antimicrobial discovery. This project aims to investigate the synthesis of novel glyoxylamide antimicrobial peptide mimics that have the capacity to disrupt bacterial membranes. The innovative interdisciplinary approach expects to generate new, small molecular antimicrobial mimics that possess a low propensity for developing resistance. This could allow control of the unwanted microbial activity without the use of antibiotics that select for the resistant organisms. It will pro ....New scaffolds for antimicrobial discovery. This project aims to investigate the synthesis of novel glyoxylamide antimicrobial peptide mimics that have the capacity to disrupt bacterial membranes. The innovative interdisciplinary approach expects to generate new, small molecular antimicrobial mimics that possess a low propensity for developing resistance. This could allow control of the unwanted microbial activity without the use of antibiotics that select for the resistant organisms. It will provide excellent training for young researchers and lead to high quality research publications in international journals.Read moreRead less
Molecular Interactions with an antibiotic target in DNA replication. This project aims to develop and use new technologies to address mechanistic aspects of anti-bacterial compounds in development, and of the development of resistance to them. The project will focus on the sliding clamp subunit of the bacterial replicative polymerase by studying its association with many other proteins in vitro and in vivo, using novel techniques in solid-state NMR, single-molecule fluorescence and molecular mic ....Molecular Interactions with an antibiotic target in DNA replication. This project aims to develop and use new technologies to address mechanistic aspects of anti-bacterial compounds in development, and of the development of resistance to them. The project will focus on the sliding clamp subunit of the bacterial replicative polymerase by studying its association with many other proteins in vitro and in vivo, using novel techniques in solid-state NMR, single-molecule fluorescence and molecular microbiology. The outcomes are expected to be an increased understanding of bacterial DNA replication and mechanisms of antibiotic action and resistance. This project expects to generate new knowledge to assist in combatting antibiotic resistance in Gram-negative bacterial pathogens.Read moreRead less
Discovery Early Career Researcher Award - Grant ID: DE190100668
Funder
Australian Research Council
Funding Amount
$422,574.00
Summary
Cysteamine dioxygenases: novel oxygen sensors implicated in hypoxia? This project aims to characterise and manipulate a novel oxygen sensing system, the cysteamine dioxygenases, to help understand how mammalian cells respond to low oxygen concentrations, a condition known as hypoxia. A number of the world’s most destructive diseases can impair oxygen delivery, altering biochemical landscapes. By understanding how cells respond to fluctuations in oxygen, the project expects to develop effective m ....Cysteamine dioxygenases: novel oxygen sensors implicated in hypoxia? This project aims to characterise and manipulate a novel oxygen sensing system, the cysteamine dioxygenases, to help understand how mammalian cells respond to low oxygen concentrations, a condition known as hypoxia. A number of the world’s most destructive diseases can impair oxygen delivery, altering biochemical landscapes. By understanding how cells respond to fluctuations in oxygen, the project expects to develop effective methods to treat these detrimental conditions. Characterisation of the cysteamine dioxygenases could establish a novel mechanism by which cells monitor changes in oxygen, assisting in understanding hypoxia and disease. The project will also enable new cysteine initiating substrates to be identified, allowing the full impact of this regulatory process to be appreciated in mammals.Read moreRead less
The Development of Computer-Aided Molecular Modelling and Drug Design Techniques for Flexible Enzyme Targets - New Anti-HIV Agents. The dynamic motion of proteins upon binding of small molecules is crucial in many cases for the function of the protein or for the function of drugs acting upon the protein. Current methods in computer-aided design of small molecules binding to proteins do not take this protein flexibility fully into account. This project intends to develop molecular dynamics simula ....The Development of Computer-Aided Molecular Modelling and Drug Design Techniques for Flexible Enzyme Targets - New Anti-HIV Agents. The dynamic motion of proteins upon binding of small molecules is crucial in many cases for the function of the protein or for the function of drugs acting upon the protein. Current methods in computer-aided design of small molecules binding to proteins do not take this protein flexibility fully into account. This project intends to develop molecular dynamics simulation techniques for this purpose, initially using the HIV reverse transcriptase enzyme as the target protein. The methods developed will, however, be universally applicable. The project further aims to design, synthesise and test novel medicinal agents specifically against drug resistance in HIV.Read moreRead less
An Open Source Approach to Understanding an Important Parasite Ion Pump. This project plans to synthesise new compounds that bind the protein ATP4, an essential ion pump in the malaria parasite. It plans to generate a three-dimensional map to understand how these compounds stop ATP4 from working. Several promising new medicines for malaria target ATP4, yet we do not understand properly how they do so. The project’s intended aims will be achieved using new methods in synthetic chemistry and membr ....An Open Source Approach to Understanding an Important Parasite Ion Pump. This project plans to synthesise new compounds that bind the protein ATP4, an essential ion pump in the malaria parasite. It plans to generate a three-dimensional map to understand how these compounds stop ATP4 from working. Several promising new medicines for malaria target ATP4, yet we do not understand properly how they do so. The project’s intended aims will be achieved using new methods in synthetic chemistry and membrane biology, and by leveraging global scientific inputs through online research methods allowing anyone to participate.Read moreRead less
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE0453832
Funder
Australian Research Council
Funding Amount
$550,910.00
Summary
New directions in biomolecular mass spectrometry. The combined UoW/ANU mass spectrometry facility supports a range of research projects in high priority areas including proteomics, mechanisms of aging, anticancer drugs and pathogenicity. The facility has several key deficiencies: 1) the ability to study very high molecular weight biomolecular complexes, 2) the ability to study ion-molecule interactions that have implications in mechanisms of chemistry in nature, and 3) researchers at ANU lack es ....New directions in biomolecular mass spectrometry. The combined UoW/ANU mass spectrometry facility supports a range of research projects in high priority areas including proteomics, mechanisms of aging, anticancer drugs and pathogenicity. The facility has several key deficiencies: 1) the ability to study very high molecular weight biomolecular complexes, 2) the ability to study ion-molecule interactions that have implications in mechanisms of chemistry in nature, and 3) researchers at ANU lack essential walk-up access to high sensitivity protein sequence analysis (MS/MS). The placement of resources that address these deficiencies in one geographical region and collaboration between these institutions will produce a research interaction unique in Australia.Read moreRead less
Discovery of bioactive natural substances from uncultured bacteria and their production using photosynthetic reactor technology. The range and rate of natural product discovery is the limiting factor in developing new therapies for cancer and infectious disease. This research will enable the discovery of new drugs, coupled to their production in a photosynthetic expression system. This represents a truly “green” and sustainable technology for the pharmaceutical industry.
Overcoming antibiotic resistance: rapid discovery of new antibacterial drug targets using chemical proteomics. The prevalence of multidrug-resistant bacteria in the community is a critical public health issue and there is an urgent and compelling need for new antibiotics with novel modes of action to combat these deadly superbugs. While antibiotics from nature have long been a mainstay of the pharmaceutical industry, their development as drugs can be challenging as their cellular targets and mod ....Overcoming antibiotic resistance: rapid discovery of new antibacterial drug targets using chemical proteomics. The prevalence of multidrug-resistant bacteria in the community is a critical public health issue and there is an urgent and compelling need for new antibiotics with novel modes of action to combat these deadly superbugs. While antibiotics from nature have long been a mainstay of the pharmaceutical industry, their development as drugs can be challenging as their cellular targets and modes of action are frequently unknown. In this project, innovative chemical proteomics approaches will be used to rapidly identify and characterise the cellular targets and modes of action of both newly discovered and historic antibiotic natural products, thereby overcoming this bottleneck and accelerating the development of next-generation antibiotics.Read moreRead less