What's On at UWA

The inducible expression of AmpC β-lactamase is a major cause of β-lactam antibiotic resistance in several clinically relevant Gram-negative bacteria, including the opportunistic pathogen Pseudomonas aeruginosa. AmpC induction is regulated by the transcriptional regulator AmpR, which binds to the divergent ampR-ampC operon and is activated by 1,6-anhydromuramoylpeptide – an anabolite of peptidoglycan (PG) recycling that is generated by the N-acetyl-β-glucosaminidase NagZ. I will be sharing my findings into the molecular basis of ampC induction based on the structural and biophysical characterization of the archetypal AmpR protein from Citrobacter freundii (CfAmpR). CfAmpR forms a homotetramer that is stabilized by binding the intergenic region of the ampR-ampC operon, and it interacts with up to four repressor ligands (UDP-MurNAc-pentapeptide) in an apparent stepwise manner. Since NagZ generates the AmpR activator ligand, blocking its activity enhances β-lactam efficacy against bacteria with inducible AmpC systems. Crystal structures of NagZ from Burkholderia cenocepacia were determined in complex with the glycosidase inhibitor O-(2-acetamido-2- deoxy-D-glucopyranosylidene)-amino-N-phenylcarbamate (PUGNAc) and its NagZ-selective derivative ethylbutyryl-PUGNAc, 3-acetamido-4,5,6-trihydroxyazepane (MM-124) and its NagZ-selective derivative MM-156, showing that plasticity within the NagZ active site could be exploited to improve the design of inhibitors that selectively bind NagZ over functionally related human N-acetyl-β-glucosaminidases. Furthering an understanding of the role of NagZ inhibition on β-lactam resistance in P. aeruginosa, it was found that the NagZ inhibitor PUGNAc could prevent the emergence of high-level AmpC-mediated β-lactam resistance, and significantly enhanced β-lactam susceptibility in synergy with the potent β-lactamase inhibitor avibactam in an ampC derepressed P. aeruginosa strain. Collectively, this talk offers key insights into the regulatory mechanism of AmpC β-lactamase expression and explores small molecule based strategies to potentiate β-lactam efficacy against Gram-negative bacterial pathogens.

Abstract: Most cells in our bodies are embedded in a complex matrix of extracellular molecules. These tissue-specific and dynamic microenvironments are essential for the functioning of the cells. But exactly what these microenvironments, or so-called "cell niche", are doing to the cells? Can we capture the "design principles" of these complex matrices on engineered microsystems, and guide in vitro cultured cells to form and function as a tissue? Traditional two-dimensional cell culture systems have been used to investigate the roles of tissue microenviroments. But these experimental systems are often too simplistic to reflect the complexity of the natural microenvironment. On the other hand, native tissue microenvironments, such as those provided by decellularised organs, are too complex to be reverse-engineered into model systems that can be studied and applied. This talk summarises our lab's recent attempts to deconstruct tissue microenvironments into their biochemical and architectural components, and investigate the roles of each components in guiding adult stem cell differentiation. The objective of this seminar is to introduce an interdisciplinary audience to the nature and challenges of our research question, and to present some of the approaches we are using to tackle it. Discussion with the cell biologists, bioengineers, materials scientists after the talk will hopefully bring forth fresh and creative ideas on this project.

Postponed until November

Microbes and transition metals: insights into manganese and gold biogeochemical cycling

Applications of High Frequency Ultrasound and Photoacoustic Imaging in small animals- Cardiovascular Imaging & Analysis, Cancer Imaging, Kidney, Liver & Other Abdominal Organs, Reproductive, Embryo & Neonate Imaging, Ophthalmic Imaging, Image-Guided Needle Injections, Microvascular Perfusion with Contrast Agents,Molecular Imaging Techniques.

Mechanism and Application of Microbial Extracellular Electron Uptake Process

X-ray diffraction and scattering at Curtin University: Big stuff, small stuff, hot stuff, cold stuff

Unfortunately this event has been cancelled.

THIS SEMINAR HAS BEEN CANCELLED

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Molecular Phenotyping in Precision and Preventive Medicine

“Cryo-EM studies of E. coli F1Fo ATP synthase”

Catalytic synthesis with titanium and Carbenes

APR Intern connects Australia’s biggest problem solvers from a range of disciplines, enhancing the PhD experience of students by giving them the opportunity to apply their research skills within an industry context.

Exploring the materials of the solar system with Australia’s central facilities

Latest advances in nanoscale IR spectroscopy and imaging

Association of ideas about Cellular Biochemistry, Inflammation and Microsporidia

Abstract: Ageing occurs in a regulated manner and the associated gene expression changes could contribute to the onset of many diseases, either by creating a permissive environment for pathology, or by directly inducing these conditions. We identified an Age-related Gene Expression Signature (AGES) in rats, by studying a time course of gene expression throughout the lifespan of the animal. Examining multiple tissues in rats aged 6, 9, 12, 18, 21, 24 and 27 months, we demonstrated tissue-specific and common gene pathway changes. Since AGES were shared by multiple tissues, it is plausible that perturbation of a discrete cell signalling pathway can extend life span and delay age-related diseases. We next asked, what is the impact of clinically-relevant low doses of rapalog on age-related pathway changes? Rapamycin or rapalogs (e.g. RAD001) that are inhibitors of mTORC1 (mammalian target of rapamycin complex 1), have been shown to increase lifespan and forestall age-related phenotypes in multiple species, including humans. Interestingly, the effect of RAD001 on age-related gene pathways was more pronounced in kidneys compared with other examined tissues (liver, skeletal muscle and hippocampus). The majority of the age-related pathways in the kidney were counter-regulated by a low dose of RAD001, and this was accompanied by reduction of age-related renal histopathology. We also examined the impact of RAD001 on molecular pathways implicated in skeletal muscle ageing (sarcopenia). This partial inhibition of the mTORC1 pathway counteracted age-related changes in expression of several genes related to senescence, muscle atrophy and deterioration of neuromuscular junctions, plus prevented loss of muscle mass for select muscles. These studies emphasise the potential benefit of drugs that target global signalling pathways as a successful strategy to reduce the adverse consequences of ageing.

Abstract: Homeostasis of the extracellular matrix (ECM) is critical for correct organ and tissue function. It plays a critical role in normal tissue homeostasis and pathological disease progression. Both the biochemical and biomechanical properties of the ECM contribute to modulating the behaviour of resident cells and are more than just passive bystanders. In tissue diseases such as cancer, the ECM undergoes significant change. These changes, driven by both tumour and stromal cells, feed into the progression of the disease. As such, changes in the ECM mark significant transition events in disease progression. Understanding how the changing ECM facilitates tumour progression and metastasis is an important step in the development of new therapeutic approaches for the treatment of cancer.

Dr. Philipp Bayer - Eukaryotic pangenomics – where we’ve been, where we’re going.