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July 18, 2014

VIP: Importance of the 6'-Hydroxy Group and Its Configuration for Apramycin Activity

VIP: Importance of the 6'-Hydroxy Group and Its Configuration for Apramycin ActivityAppi Reddy Mandhapati, Dimitri Shcherbakov, Stefan Duscha, Andrea Vasella,* Erik C. Böttger,* David Crich*

The relative lack of success of combinatorial drug discovery platforms in the search for novel antibacterial drugs warrants a renewed focus on the optimization of established drug classes such as the aminoglycoside antibiotics. Most aminoglycosides in current use suffer from toxicity problems, the most serious of which is drug-induced ototoxicity.

Researchers in this collaboration focus on apramycin, an aminoglycoside antibiotic currently only used in veterinary medicine, that has previously been demonstrated to be substantially ototoxicity-free and efficacious in the treatment of methicillin-resistant Staphylococcus aureus in animal models. Read more...

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Recently Published Articles

  1. Diaryl-Substituted Azolylthioacetamides: Inhibitor Discovery of New Delhi Metallo-β-Lactamase-1 (NDM-1)

    Yi-Lin Zhang, Prof. Ke-Wu Yang, Ya-Jun Zhou, Alecander E. LaCuran, Prof. Peter Oelschlaeger and Prof. Michael W. Crowder

    Article first published online: 22 JUL 2014 | DOI: 10.1002/cmdc.201402249

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    New inhibitors for NDM-1: Azolylthioacetamides 118 were obtained and all of them were found to be inhibitors of metallo-β-lactamases (MβLs) L1 (Ki<2 μM). Compounds 17, 913, and 16 are mixed inhibitors of NDM-1 (Ki<7 μM), and 2, 4, 5, and 7 are broad-spectrum inhibitors of all four tested MβLs: CcrA, NDM-1, ImiS, and L1 (Ki<52 μM). Docking studies revealed that 4 and 10 coordinate to the ZnII ion(s) via the triazole moiety, while other moieties interact with the conserved active site residues Lys224 or Ser221.

  2. Structural and Biochemical Studies of Actin in Complex with Synthetic Macrolide Tail Analogues

    Dr. Jose H. Pereira, Dr. Chutima Petchprayoon, Dr. Alexander C. Hoepker, Dr. Nigel Moriarty, Dr. Sarah J. Fink, Dr. Giuseppe Cecere, Prof. Ian Paterson, Prof. Paul D. Adams and Prof. Gerard Marriott

    Article first published online: 22 JUL 2014 | DOI: 10.1002/cmdc.201402150

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    Actin’ tough: The actin filament binding and severing activities of marine macrolides are located within the hydrophobic tail region of the molecule. The synthetic tail analogue GC-04 is shown to bind to G-actin with a dissociation constant of (132±13) nM. The structure of the actin–GC-04 complex reveals the mode of tail binding within the cleft between subdomains 1 and 3.

  3. Amphiphilic Bicyclic Peptides as Cellular Delivery Agents

    Donghoon Oh, Dr. Shaban Anwar Darwish, Dr. Amir Nasrolahi Shirazi, Prof. Rakesh Kumar Tiwari and Prof. Keykavous Parang

    Article first published online: 22 JUL 2014 | DOI: 10.1002/cmdc.201402230

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    Intracellular express: An amphiphilic bicyclic peptide containing two monocyclic peptides was developed. The cellular uptake pathways were determined to be mainly clathrin- and lipid raft-caveolin-dependent endocytosis. The bicyclic peptide enhanced the delivery of a cell-impermeable negatively charged phosphopeptide and improved antiproliferative activity and retention of doxorubicin in human ovarian adenocarcinoma cells.

  4. Bis-Pyrene-Modified Unlocked Nucleic Acids: Synthesis, Hybridization Studies, and Fluorescent Properties

    Dr. Pavla Perlíková, Maria Ejlersen, Dr. Niels Langkjær and Prof. Jesper Wengel

    Article first published online: 18 JUL 2014 | DOI: 10.1002/cmdc.201402185

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    Second to none with 2 to 1: We attached two pyrenes to a single unlocked nucleic acid (UNA) monomer, one via a piperazino linker and the other directly to the 5-position of uracil. Fluorescence measurements of an oligonucleotide with two bis-pyrene UNA incorporations are able to clearly distinguish between the single stranded-form and matched and bulge-containing duplex forms.

  5. Insight into the Interactions between Novel Coumarin Derivatives and Human A3 Adenosine Receptors

    Dr. Maria João Matos, Dr. Santiago Vilar, Dr. Sonja Kachler, André Fonseca, Prof. Lourdes Santana, Prof. Eugenio Uriarte, Prof. Fernanda Borges, Dr. Nicholas P. Tatonetti and Prof. Karl-Norbert Klotz

    Article first published online: 18 JUL 2014 | DOI: 10.1002/cmdc.201402205

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    Coumarin contacts: The current work describes the synthesis and evaluation of the affinity for the four human adenosine receptor subtypes of potent and selective 3-arylcoumarins. We also present theoretical predictions of ADME properties and docking calculations for these compounds.