Design and Syntheses of Highly Potent Teixobactin Analogues against Staphylococcus aureus, Methicillin-Resistant Staphylococcus aureus (MRSA), and Vancomycin-Resistant Enterococci (VRE) in Vitro and in Vivo

  • Anish Parmar
    Anish Parmar
    School of Pharmacy, Joseph Banks Laboratories, University of Lincoln, Green Lane, Lincoln LN6 7DL, United Kingdom
    More by Anish Parmar
  • Rajamani Lakshminarayanan
    Rajamani Lakshminarayanan
    Singapore Eye Research Institute, The Academia, Discovery Tower Level 6, 20 College Road, 169857 Singapore
  • Abhishek Iyer
    Abhishek Iyer
    School of Pharmacy, Joseph Banks Laboratories, University of Lincoln, Green Lane, Lincoln LN6 7DL, United Kingdom
    Organic and Biomimetic Chemistry Research Group, Department of Organic and Macromolecular Chemistry, Ghent University, Krijgslaan 281 (S4), Ghent B-9000, Belgium
  • Venkatesh Mayandi
    Venkatesh Mayandi
    Singapore Eye Research Institute, The Academia, Discovery Tower Level 6, 20 College Road, 169857 Singapore
  • Eunice Tze Leng Goh
    Eunice Tze Leng Goh
    Singapore Eye Research Institute, The Academia, Discovery Tower Level 6, 20 College Road, 169857 Singapore
  • Daniel G. Lloyd
    Daniel G. Lloyd
    School of Life Sciences, Joseph Banks Laboratories, University of Lincoln, Green Lane, Lincoln LN6 7DL, United Kingdom
  • Madhavi Latha S. Chalasani
    Madhavi Latha S. Chalasani
    Lee Kong Chian School of Medicine, Nanyang Technological University, 636921 Singapore
  • Navin K. Verma
    Navin K. Verma
    Lee Kong Chian School of Medicine, Nanyang Technological University, 636921 Singapore
    Singapore Eye Research Institute, The Academia, Discovery Tower Level 6, 20 College Road, 169857 Singapore
  • Stephen H. Prior
    Stephen H. Prior
    School of Chemistry, Joseph Banks Laboratories, University of Lincoln, Green Lane, Lincoln LN6 7DL, United Kingdom
  • Roger W. Beuerman
    Roger W. Beuerman
    Singapore Eye Research Institute, The Academia, Discovery Tower Level 6, 20 College Road, 169857 Singapore
  • Annemieke Madder
    Annemieke Madder
    Organic and Biomimetic Chemistry Research Group, Department of Organic and Macromolecular Chemistry, Ghent University, Krijgslaan 281 (S4), Ghent B-9000, Belgium
  • Edward J. Taylor
    Edward J. Taylor
    School of Life Sciences, Joseph Banks Laboratories, University of Lincoln, Green Lane, Lincoln LN6 7DL, United Kingdom
  • , and 
  • Ishwar Singh*
    Ishwar Singh
    School of Pharmacy, Joseph Banks Laboratories, University of Lincoln, Green Lane, Lincoln LN6 7DL, United Kingdom
    *E-mail: [email protected]
    More by Ishwar Singh
Cite this: J. Med. Chem. 2018, 61, 5, 2009–2017
Publication Date (Web):January 24, 2018
https://doi.org/10.1021/acs.jmedchem.7b01634
Copyright © 2018 American Chemical Society
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Abstract

The cyclic depsipeptide, teixobactin, kills a number of Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), and Mycobacterium tuberculosis without detectable resistance. To date, teixobactin is the only molecule in its class that has shown in vivo antibacterial efficacy. In this work, we designed and synthesized 10 new in vivo ready teixobactin analogues. These analogues showed highly potent antibacterial activities against Staphylococcus aureus, MRSA, and vancomycin-resistant enterococci (VRE) in vitro. One analogue, d-Arg4-Leu10-teixobactin, 2, was found to be noncytotoxic in vitro and in vivo. Moreover, topical instillation of peptide 2 in a mouse model of S. aureus keratitis decreased the bacterial bioburden (>99.0% reduction) and corneal edema significantly as compared to untreated mouse corneas. Collectively, our results have established the high therapeutic potential of a teixobactin analogue in attenuating bacterial infections and associated severities in vivo.

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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.7b01634.

  • Peptides, HPLC, LC-MS analysis, NMR analysis, in vitro antibacterial assay (MIC, MBC, time-kill kinetics), in vitro cytotoxicity assay, in vivo cytotoxicity assay, and in vivo antibacterial efficacy (PDF)

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