A5056677621- Protein Structure and Dynamics
- Vibrio bacteria research studies
- Antibiotic Resistance in Bacteria
- Endoplasmic Reticulum Stress and Disease
- Bacterial Genetics and Biotechnology
- Malaria Research and Control
- Biochemical and Molecular Research
- Computational Drug Discovery Methods
- Click Chemistry and Applications
- Microbial Natural Products and Biosynthesis
- Enzyme Structure and Function
- Escherichia coli research studies
- Salmonella and Campylobacter epidemiology
- Bacteriophages and microbial interactions
- Mosquito-borne diseases and control
- Redox biology and oxidative stress
- Research on Leishmaniasis Studies
- Metabolomics and Mass Spectrometry Studies
- Biosimilars and Bioanalytical Methods
- Advanced NMR Techniques and Applications
- Biochemical and Structural Characterization
- Hepatitis B Virus Studies
- Mass Spectrometry Techniques and Applications
- Heme Oxygenase-1 and Carbon Monoxide
- Trace Elements in Health
La Trobe University
2017-2025
Monash University
2013-2019
The University of Adelaide
2014
Disulfide bond protein A (DsbA) plays a pivotal role in catalysing the formation of disulfide bonds within periplasm most Gram-negative bacteria. As this process is required for folding multiple virulence-associated proteins, inhibitors DsbA have potential to be developed as novel anti-virulence agents. Despite extensive efforts develop high-affinity targeting canonical substrate-binding site, success has been limited. In current work, we describe dynamics-driven fragment discovery approach....
DsbA catalyzes disulfide bond formation in secreted and outer membrane proteins bacteria. In pathogens, is a major facilitator of virulence constituting target for antivirulence antimicrobial development. However, many pathogens encode multiple diverse enzymes factor folding during infection. The aim this study was to determine whether our recently identified inhibitors Escherichia coli K-12 can inhibit the found two important human attenuate their virulence.DsbA from chemical classes...
We established an efficient means of probing ligand-induced conformational change in the malaria drug target AMA1 using 19F NMR. was labeled with 5-fluorotryptophan (5F-Trp), and resulting 5F-Trp resonances were assigned by mutagenesis native Trp residues. By introducing additional residues at strategic sites within a ligand-responsive loop, we detected distinct consequences when various peptide small-molecule ligands bound AMA1. Our results demonstrate increase flexibility this loop caused...
Autotransporters are the largest family of outer membrane and secreted proteins in Gram-negative bacteria. Most autotransporters localised to bacterial surface where they promote colonisation host epithelial surfaces. Here we present crystal structure UpaB, an autotransporter that is known contribute uropathogenic E. coli (UPEC) urinary tract. We provide evidence UpaB can interact with glycosaminoglycans fibronectin. Unique modifications its core β-helical create a groove on one side protein...
A fragment-based drug discovery approach was taken to target the thiol-disulfide oxidoreductase enzyme DsbA from Escherichia coli (EcDsbA). This is critical for correct folding of virulence factors in many pathogenic Gram-negative bacteria, and small molecule inhibitors can potentially be developed as anti-virulence compounds. Biophysical screening a library fragments identified several classes with affinity EcDsbA. One hit high mM affinity, 2-(6-bromobenzofuran-3-yl)acetic acid (6),...
A bottleneck in fragment-based lead development is the lack of systematic approaches to elaborate initial fragment hits, which usually bind with low affinity their target. Herein, we describe an analysis using X-ray crystallography a diverse library compounds prepared microscale parallel synthesis. This approach yielded 8-fold increase and detailed structural information for resulting complex, providing efficient broadly applicable early development.
An improved synthesis of biotinol-5′-AMP, an acyl-AMP mimic the natural reaction intermediate biotin protein ligase (BPL), is reported. This compound was shown to be a pan inhibitor BPLs from series clinically important bacteria, particularly Staphylococcus aureus and Mycobacterium tuberculosis, kinetic analysis revealed it competitive against substrate biotin. Biotinol-5′-AMP also exhibits antibacterial activity panel clinical isolates S. M. tuberculosis with MIC values 1–8 0.5–2.5 μg/mL,...
Apical membrane antigen 1 (AMA1) of the human malaria parasite Plasmodium falciparum has been implicated in invasion host erythrocyte. It interacts with malarial rhoptry neck (RON) proteins moving junction that forms between cell and invading parasite. Agents block this interaction inhibit may serve as promising leads for anti-malarial drug development. The invasion-inhibitory peptide R1 binds to a hydrophobic cleft on AMA1, which is an attractive target site small molecules invasion. In...
Abstract Apical membrane antigen 1 (AMA1) is essential for the invasion of host cells by malaria parasites. Several small‐molecule ligands have been shown to bind a conserved hydrophobic cleft in Plasmodium falciparum AMA1. However, lack detailed structural information on binding pose these molecules has hindered their further optimisation as inhibitors. We developed spin‐labelled peptide based RON2, native partner AMA1, probe sites compounds Pf The crystal structure this bound AMA1 shows...
The formation of disulphide bonds is an essential step in the folding many proteins that enter secretory pathway; therefore, it not surprising eukaryotic and prokaryotic organisms have dedicated enzymatic systems to catalyse this process. In bacteria, one such enzyme bond-forming protein A (DsbA), a thioredoxin-like thiol oxidase catalyses oxidative required for virulence fitness. large body work on DsbA proteins, particularly Escherichia coli (EcDsbA), has demonstrated key role...
The worldwide incidence of neisserial infections, particularly gonococcal is increasingly associated with antibiotic-resistant strains. In particular, extensively drug-resistant Neisseria gonorrhoeae strains that are resistant to third-generation cephalosporins a major public health concern. There pressing clinical need identify new targets for the development antibiotics effective against Neisseria-specific processes. this study, we report bacterial disulfide reductase DsbD highly prevalent...
Aims: Thioredoxin (TRX)-fold proteins are ubiquitous in nature. This redox scaffold has evolved to enable a variety of functions, including regulation, protein folding, and oxidative stress defense. In bacteria, the TRX-like disulfide bond (Dsb) family mediates folding multiple required for fitness pathogenic potential. Conventionally, Dsb have specific functions with monomeric dimeric Dsbs exclusively catalyzing thiol oxidation isomerization, respectively. contrasts eukaryotic forming...
Aggregation of small organic compounds is a problem encountered in variety assay screening formats where it often results detection false positives. A saturation transfer difference-NMR-detected screen commercially available fragment library, followed by biochemical assay, identified several inhibitors the enzyme ketopantoate reductase. These were subsequently revealed to be aggregation-based Modification addition detergent difference-NMR experiments allowed an format developed that resulted...
DsbA enzymes catalyze oxidative folding of proteins that are secreted into the periplasm Gram-negative bacteria, and they indispensable for virulence human pathogens such as Vibrio cholerae Escherichia coli. Therefore, targeting represents an attractive approach to control bacterial virulence. X-ray crystal structures reveal share a similar fold, however, hydrophobic groove adjacent active site, which is implicated in substrate binding, shorter flatter structure V. (VcDsbA) compared E. coli...
Abstract Structures of protein–ligand complexes provide critical information for drug design. Most complex structures are determined using X-ray crystallography, but where crystallography is not able to generate a structure complex, NMR often the best alternative. However, available tools enable rapid and robust determination by currently limited. This leads situations projects either discontinued or pursued without structural data, rendering task more difficult. We previously reported...
DsbA enzymes catalyze oxidative folding of proteins that are secreted into the periplasm Gram-negative bacteria, and they indispensable for virulence human pathogens such as Vibrio cholerae Escherichia coli. Therefore, targeting represents an attractive approach to control bacterial virulence. X-ray crystal structures reveal share a similar fold, however, hydrophobic groove adjacent active site, which is implicated in substrate binding, shorter flatter structure V. (VcDsbA) compared E. coli...
Antibiotic resistance is growing to dangerously high levels and poses a serious threat global public health.The emergence spread of mechanisms all antibiotics introduced into the clinic jeopardize effectiveness current treatments.Traditionally, have been designed inhibit bacterial viability or impair their growth; these induce strong selection pressure for development.To overcome this problem, an alternate approach disarm virulence without killing them, which potentially reduces delays...
DsbA enzymes catalyze oxidative folding of proteins that are secreted into the periplasm Gram-negative bacteria, and they indispensable for virulence human pathogens such as Vibrio cholerae Escherichia coli. Therefore, targeting represents an attractive approach to control bacterial virulence. X-ray crystal structures reveal share a similar fold, however, hydrophobic groove adjacent active site, which is implicated in substrate binding, shorter flatter structure V. (VcDsbA) compared E. coli...