Design of Next Generation Polymyxins with Lower Toxicity: The Discovery of SPR206Click to copy article linkArticle link copied!
- Pamela Brown*Pamela Brown*E-mail: [email protected]Cantab Anti-Infectives Ltd., BioPark, Broadwater Road, Welwyn Garden City, Hertfordshire AL7 3AX, United KingdomSpero Therapeutics Inc., 675 Massachusetts Avenue, 14th Floor, Cambridge, Massachusetts 02139, United StatesMore by Pamela Brown
- Elizabeth AbbottElizabeth AbbottCantab Anti-Infectives Ltd., BioPark, Broadwater Road, Welwyn Garden City, Hertfordshire AL7 3AX, United KingdomMore by Elizabeth Abbott
- Omar AbdulleOmar AbdulleCantab Anti-Infectives Ltd., BioPark, Broadwater Road, Welwyn Garden City, Hertfordshire AL7 3AX, United KingdomMore by Omar Abdulle
- Steven BoakesSteven BoakesCantab Anti-Infectives Ltd., BioPark, Broadwater Road, Welwyn Garden City, Hertfordshire AL7 3AX, United KingdomMore by Steven Boakes
- Scott ColemanScott ColemanSpero Therapeutics Inc., 675 Massachusetts Avenue, 14th Floor, Cambridge, Massachusetts 02139, United StatesMore by Scott Coleman
- Naomi DivallNaomi DivallCantab Anti-Infectives Ltd., BioPark, Broadwater Road, Welwyn Garden City, Hertfordshire AL7 3AX, United KingdomMore by Naomi Divall
- Esther DuperchyEsther DuperchyCantab Anti-Infectives Ltd., BioPark, Broadwater Road, Welwyn Garden City, Hertfordshire AL7 3AX, United KingdomMore by Esther Duperchy
- Stephen MossStephen MossEurofins Selcia Drug Discovery, U.K., Fyfield Business & Research Park, Fyfield Road, Ongar, Essex CM5 0GS, United KingdomMore by Stephen Moss
- Dean RiversDean RiversCantab Anti-Infectives Ltd., BioPark, Broadwater Road, Welwyn Garden City, Hertfordshire AL7 3AX, United KingdomMore by Dean Rivers
- Mona SimonovicMona SimonovicCantab Anti-Infectives Ltd., BioPark, Broadwater Road, Welwyn Garden City, Hertfordshire AL7 3AX, United KingdomMore by Mona Simonovic
- Jaspal SinghJaspal SinghCantab Anti-Infectives Ltd., BioPark, Broadwater Road, Welwyn Garden City, Hertfordshire AL7 3AX, United KingdomMore by Jaspal Singh
- Steven StanwaySteven StanwayEurofins Selcia Drug Discovery, U.K., Fyfield Business & Research Park, Fyfield Road, Ongar, Essex CM5 0GS, United KingdomMore by Steven Stanway
- Antoinette WilsonAntoinette WilsonEurofins Selcia Drug Discovery, U.K., Fyfield Business & Research Park, Fyfield Road, Ongar, Essex CM5 0GS, United KingdomMore by Antoinette Wilson
- Michael J. DawsonMichael J. DawsonCantab Anti-Infectives Ltd., BioPark, Broadwater Road, Welwyn Garden City, Hertfordshire AL7 3AX, United KingdomSpero Therapeutics Inc., 675 Massachusetts Avenue, 14th Floor, Cambridge, Massachusetts 02139, United StatesMore by Michael J. Dawson
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.
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