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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. Singly Modified Amikacin and Tobramycin Derivatives Show Increased rRNA A-Site Binding and Higher Potency against Resistant Bacteria

    Dr. Richard J. Fair, Dr. Lisa S. McCoy, Dr. Mary E. Hensler, Bernice Aguilar, Prof. Dr. Victor Nizet and Prof. Dr. Yitzhak Tor

    Article first published online: 23 JUL 2014 | DOI: 10.1002/cmdc.201402175

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    Irresistible! Amikacin and tobramycin are two clinically useful RNA-targeting aminoglycosides. Modified versions of these compounds showed equal to or better potency against certain resistant bacterial strains, while their eukaryotic cytotoxicity remained identical to that of the parent antibiotics.

  2. Conjugation to Albumin-Binding Molecule Tags as a Strategy to Improve Both Efficacy and Pharmacokinetic Properties of the Complement Inhibitor Compstatin

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    Article first published online: 23 JUL 2014 | DOI: 10.1002/cmdc.201402212

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    Two birds with one stone: Conjugates of the complement inhibitor compstatin and albumin-binding molecules were designed to improve the drug’s pharmacokinetic properties. The resulting chimera ABM2-Cp20 indeed showed improved plasma protein binding, yet also largely enhanced target affinity, producing the most potent compstatin analogue so far.

  3. 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.

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

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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.

  5. Amphiphilic Bicyclic Peptides as Cellular Delivery Agents

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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.

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