2. Academic Validation
  3. Design of Next Generation Polymyxins with Lower Toxicity: The Discovery of SPR206

Design of Next Generation Polymyxins with Lower Toxicity: The Discovery of SPR206

  • ACS Infect Dis. 2019 Oct 11;5(10):1645-1656. doi: 10.1021/acsinfecdis.9b00217.
Pamela Brown 1 2,  Elizabeth Abbott 1,  Omar Abdulle 1,  Steven Boakes 1,  Scott Coleman 2,  Naomi Divall 1,  Esther Duperchy 1,  Stephen Moss 3,  Dean Rivers 1,  Mona Simonovic 1,  Jaspal Singh 1,  Steven Stanway 3,  Antoinette Wilson 3,  Michael J Dawson 1 2
Affiliations

Affiliations

  • 1 Cantab Anti-Infectives Ltd. , BioPark, Broadwater Road , Welwyn Garden City , Hertfordshire AL7 3AX , United Kingdom.
  • 2 Spero Therapeutics Inc. , 675 Massachusetts Avenue , 14th Floor, Cambridge , Massachusetts 02139 , United States.
  • 3 Eurofins Selcia Drug Discovery, U.K. , Fyfield Business & Research Park, Fyfield Road , Ongar , Essex CM5 0GS , United Kingdom.
PMID: 31525992 DOI: 10.1021/acsinfecdis.9b00217
Abstract

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.

Keywords

Gram-negative; antibacterials; antimicrobial resistance; multidrug-resistant bacteria; nephrotoxicity; polymyxin.

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