Pharmacology and Therapeutics - Research Publications

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    Structure of micelle bound cationic peptides by NMR spectroscopy using a lanthanide shift reagent
    Swarbrick, JD ; Karas, JA ; Li, J ; Velkov, T (Royal Society of Chemistry, 2020-03-07)
    [Tm(DPA)3]3- was used to generate multiple, paramagnetic nuclear Overhauser effect NMR spectra of cationic peptides when weakly bound to a lipopolysaccharide micelle. Increased spectral resolution combined with a marked increase in the number of distance restraints yielded high resolution structures of polymyxin and MSI-594 in the liposaccharide bound state.
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    1,3-Dichloroacetone: A Robust Reagent for Preparing Bicyclic Peptides
    Lin, Q ; Hopper, D ; Zhang, H ; Qoon, JS ; Shen, Z ; Karas, JA ; Hughes, RA ; Northfield, SE (AMER CHEMICAL SOC, 2020-02-04)
    The chemical synthesis of cyclic peptides is a well-established area of research. This has been further expanded by development of bio-orthogonal reactions that enable access to peptides of greater structural complexity. One approach utilizes 1,3-dichloroacetone to selectively link free cysteine side-chains with an acetone-like bridge via an SN2 reaction. Here, we have used this reaction to dimerize cyclic peptide monomers to create novel bicyclic dimeric peptides. We investigated a range of reaction parameters to identify the optimal dimerization conditions for our model systems. One of the acetone-linked dimeric peptides was analyzed for proteolytic stability in human serum and was observed to still be fully intact after 48 h. This study provides valuable insights into the application of 1,3-dichloroacetone as a tool in the synthesis of complex, multicyclic peptides.
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    The Antimicrobial Activity of Cannabinoids
    Karas, JA ; Wong, LJM ; Paulin, OKA ; Mazeh, AC ; Hussein, MH ; Li, J ; Velkov, T (MDPI AG, 2020-07-13)
    A post-antibiotic world is fast becoming a reality, given the rapid emergence of pathogens that are resistant to current drugs. Therefore, there is an urgent need to discover new classes of potent antimicrobial agents with novel modes of action. Cannabis sativa is an herbaceous plant that has been used for millennia for medicinal and recreational purposes. Its bioactivity is largely due to a class of compounds known as cannabinoids. Recently, these natural products and their analogs have been screened for their antimicrobial properties, in the quest to discover new anti-infective agents. This paper seeks to review the research to date on cannabinoids in this context, including an analysis of structure–activity relationships. It is hoped that it will stimulate further interest in this important issue.
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    The Killing Mechanism of Teixobactin against Methicillin-Resistant Staphylococcus aureus: an Untargeted Metabolomics Study
    Hussein, M ; Karas, JA ; Schneider-Futschik, EK ; Chen, F ; Swarbrick, J ; Paulin, OKA ; Hoyer, D ; Baker, M ; Zhu, Y ; Li, J ; Velkov, T ; Lloyd, KG (American Society for Microbiology, 2020)
    Antibiotics have served humankind through their use in modern medicine as effective treatments for otherwise fatal bacterial infections. Teixobactin is a first member of newly discovered natural antibiotics that was recently identified from a hitherto-unculturable soil bacterium, Eleftheria terrae, and recognized as a potent antibacterial agent against various Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci. The most distinctive characteristic of teixobactin as an effective antibiotic is that teixobactin resistance could not be evolved in a laboratory setting. It is purported that teixobactin’s “resistance-resistant” mechanism of action includes binding to the essential bacterial cell wall synthesis building blocks lipid II and lipid III. In the present study, metabolomics was used to investigate the potential metabolic pathways involved in the mechanisms of antibacterial activity of the synthetic teixobactin analogue Leu10-teixobactin against a MRSA strain, S. aureus ATCC 700699. The metabolomes of S. aureus ATCC 700699 cells 1, 3, and 6 h following treatment with Leu10-teixobactin (0.5 μg/ml, i.e., 0.5× MIC) were compared to those of the untreated controls. Leu10-teixobactin significantly perturbed bacterial membrane lipids (glycerophospholipids and fatty acids), peptidoglycan (lipid I and II) metabolism, and cell wall teichoic acid (lipid III) biosynthesis as early as after 1 h of treatment, reflecting an initial activity on the cell envelope. Concordant with its time-dependent antibacterial killing action, Leu10-teixobactin caused more perturbations in the levels of key intermediates in pathways of amino-sugar and nucleotide-sugar metabolism and their downstream peptidoglycan and teichoic acid biosynthesis at 3 and 6 h. Significant perturbations in arginine metabolism and the interrelated tricarboxylic acid cycle, histidine metabolism, pantothenate, and coenzyme A biosynthesis were also observed at 3 and 6 h. To conclude, this is the first study to provide novel metabolomics mechanistic information, which lends support to the development of teixobactin as an antibacterial drug for the treatment of multidrug-resistant Gram-positive infections
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    Nuclear Magnetic Resonance Study of the Peptide FRANCESSEPAROVIC
    Karas, JA ; Keizer, DW ; Sani, M-A (CSIRO PUBLISHING, 2020-01-01)
    As an eminent ambassador of STEM and renowned NMR spectroscopist, Frances Separovic is an internationally famous name, but could it also be a valuable membrane-active peptide sequence? Her name has been used as an amino acid sequence (FS), successfully synthesised, oxidised, and put into contact with membrane models to investigate any serendipitous activity. The 3D structure of the cyclic FS was determined in dodecylphosphocholine (DPC) micelles by solution NMR spectroscopy. FS displayed a twisted bend separating a helical stretch and an unstructured segment. Using solid-state NMR spectroscopy, the effect of FS on 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and 1,2-dimyristoyl-sn-glycero-3-phosphoserine (DMPS) lipid bilayers was studied. FS did not strongly disturb the neutral membrane surface but likely inserted into their hydrophobic core without a strong effect on the lipid dynamics, while perturbation of the negatively charged membranes remained at the headgroup interface with a strong effect on the lipid dynamics. This study demonstrated that FS is a candidate for discovering potential future therapeutic activities.