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Design of Next Generation Polymyxins with Lower Toxicity: The Discovery of SPR206
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    Design of Next Generation Polymyxins with Lower Toxicity: The Discovery of SPR206
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    • Pamela Brown*
      Pamela Brown
      Cantab Anti-Infectives Ltd., BioPark, Broadwater Road, Welwyn Garden City, Hertfordshire AL7 3AX, United Kingdom
      Spero Therapeutics Inc., 675 Massachusetts Avenue, 14th Floor, Cambridge, Massachusetts 02139, United States
      *E-mail: [email protected]
      More by Pamela Brown
    • Elizabeth Abbott
      Elizabeth Abbott
      Cantab Anti-Infectives Ltd., BioPark, Broadwater Road, Welwyn Garden City, Hertfordshire AL7 3AX, United Kingdom
    • Omar Abdulle
      Omar Abdulle
      Cantab Anti-Infectives Ltd., BioPark, Broadwater Road, Welwyn Garden City, Hertfordshire AL7 3AX, United Kingdom
      More by Omar Abdulle
    • Steven Boakes
      Steven Boakes
      Cantab Anti-Infectives Ltd., BioPark, Broadwater Road, Welwyn Garden City, Hertfordshire AL7 3AX, United Kingdom
    • Scott Coleman
      Scott Coleman
      Spero Therapeutics Inc., 675 Massachusetts Avenue, 14th Floor, Cambridge, Massachusetts 02139, United States
    • Naomi Divall
      Naomi Divall
      Cantab Anti-Infectives Ltd., BioPark, Broadwater Road, Welwyn Garden City, Hertfordshire AL7 3AX, United Kingdom
      More by Naomi Divall
    • Esther Duperchy
      Esther Duperchy
      Cantab Anti-Infectives Ltd., BioPark, Broadwater Road, Welwyn Garden City, Hertfordshire AL7 3AX, United Kingdom
    • Stephen Moss
      Stephen Moss
      Eurofins Selcia Drug Discovery, U.K., Fyfield Business & Research Park, Fyfield Road, Ongar, Essex CM5 0GS, United Kingdom
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    • Dean Rivers
      Dean Rivers
      Cantab Anti-Infectives Ltd., BioPark, Broadwater Road, Welwyn Garden City, Hertfordshire AL7 3AX, United Kingdom
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    • Mona Simonovic
      Mona Simonovic
      Cantab Anti-Infectives Ltd., BioPark, Broadwater Road, Welwyn Garden City, Hertfordshire AL7 3AX, United Kingdom
    • Jaspal Singh
      Jaspal Singh
      Cantab Anti-Infectives Ltd., BioPark, Broadwater Road, Welwyn Garden City, Hertfordshire AL7 3AX, United Kingdom
      More by Jaspal Singh
    • Steven Stanway
      Steven Stanway
      Eurofins Selcia Drug Discovery, U.K., Fyfield Business & Research Park, Fyfield Road, Ongar, Essex CM5 0GS, United Kingdom
    • Antoinette Wilson
      Antoinette Wilson
      Eurofins Selcia Drug Discovery, U.K., Fyfield Business & Research Park, Fyfield Road, Ongar, Essex CM5 0GS, United Kingdom
    • Michael J. Dawson
      Michael J. Dawson
      Cantab Anti-Infectives Ltd., BioPark, Broadwater Road, Welwyn Garden City, Hertfordshire AL7 3AX, United Kingdom
      Spero Therapeutics Inc., 675 Massachusetts Avenue, 14th Floor, Cambridge, Massachusetts 02139, United States
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    ACS Infectious Diseases

    Cite this: ACS Infect. Dis. 2019, 5, 10, 1645–1656
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    https://doi.org/10.1021/acsinfecdis.9b00217
    Published September 17, 2019
    Copyright © 2019 American Chemical Society

    Abstract

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    Polymyxins are an important class of antibiotics for the treatment of bacterial infections due to multidrug resistant Gram-negative pathogens. However, their clinical utility is limited by nephrotoxicity. Here, we report a series of promising next generation polymyxin nonapeptides identified on the basis of our understanding of the relationship of structure with activity, cytotoxicity, and kidney compartment accumulation. We demonstrate that nonapeptides with an amine-containing N-terminal moiety of specific regio- and stereochemistry possess superior in vitro activity, together with lower cytotoxicity compared to polymyxin B. We further demonstrate that compounds with a β-branched aminobutyrate N-terminus with an aryl substituent offer a promising combination of low cytotoxicity and kidney exposure, leading to low toxicity in the mouse. From this series, SPR206 has been selected as a development candidate.

    Copyright © 2019 American Chemical Society

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    Supporting Information

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsinfecdis.9b00217.

    • Syntheses of carboxylic acids, chiral separation of 3-{[(tert-butoxycarbonyl)amino]methyl}-4-phenylbutanoic acid, confirmation of stereochemistry by small molecule X-ray crystallography, syntheses of dipeptides, characterization of final compounds 243, 46, and 47, and mouse renal toxicity of compounds 20, 22, and 24 (PDF)

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    This article is cited by 68 publications.

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    ACS Infectious Diseases

    Cite this: ACS Infect. Dis. 2019, 5, 10, 1645–1656
    Click to copy citationCitation copied!
    https://doi.org/10.1021/acsinfecdis.9b00217
    Published September 17, 2019
    Copyright © 2019 American Chemical Society

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