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Discovery of Peptide Antibiotics Composed of d-Amino Acids

  • Emel Adaligil
    Emel Adaligil
    Department of Chemistry, Tufts University, Medford, Massachusetts 02155, United States
  • Kalyani Patil
    Kalyani Patil
    Department of Chemistry, Tufts University, Medford, Massachusetts 02155, United States
  • Marissa Rodenstein
    Marissa Rodenstein
    Department of Chemistry, Tufts University, Medford, Massachusetts 02155, United States
  • , and 
  • Krishna Kumar*
    Krishna Kumar
    Department of Chemistry, Tufts University, Medford, Massachusetts 02155, United States
    Department of Biomedical Engineering, Tufts University, Medford, Massachusetts 02155, United States
    Cancer Center, Tufts Medical Center, Boston, Massachusetts 02110, United States
    *E-mail: [email protected]
Cite this: ACS Chem. Biol. 2019, 14, 7, 1498–1506
Publication Date (Web):June 3, 2019
https://doi.org/10.1021/acschembio.9b00234
Copyright © 2019 American Chemical Society

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    Abstract

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    A paucity of viable programs and pipelines for the discovery of new antibiotics poses a significant public health threat. The emergence of resistant strains against vancomycin is particularly dangerous in hospital settings. Here, we report the design of enantiomeric targets based on bacterial cell wall biosynthesis precursors that allow for selection and identification of short linear, cyclic and bicyclic peptides that are composed of d-amino acids. These compounds are active against Staphylococcus aureus, Methicillin-resistant S. aureus, and vancomycin-resistant Enterococci that possess moderately high antibacterial activity and furthermore display no toxicity to both human red blood cells and mammalian cells at these concentrations. This ‘mirror image phage display’ approach yielded templates that can serve as scaffolds for further improvements in activity-based structural modifications. This strategy has the potential to provide a new class of antimicrobials that are metabolically stable and have the promise for oral delivery. The use of this platform combined with traditional medicinal chemistry approaches could rapidly yield large numbers of new therapeutic lead compounds.

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acschembio.9b00234.

    • Experimental procedures of the synthesis and spectroscopic data for target molecules (Cep-1, Ala-2, Ala-3, and Ala-4), phage display screening protocols, chemical synthesis of peptides, antibacterial activity assays, cytotoxicity assays, protease stability assays, hemolytic activity, and accumulation of bacterial cell wall assays. Figures S1–S21 and Tables S1–S4 (PDF)

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    15. I. B. Nikitina, I. V. Goretova, I. V. Fedoseev. Through the Looking Glass of Biotechnology: D-Proteins as Objects of Patent Protection. Russian Journal of Bioorganic Chemistry 2021, 47 (5) , 1014-1019. https://doi.org/10.1134/S1068162021050320
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