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

Polymyxins are an important class of antibiotics for the treatment of bacterial infections due to multi-drug resistant Gram-negative pathogens. However, their clinical utility is limited by nephrotoxicity. Here we report a series of promising next-generation polymyxin nonapeptides identified based on 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 beta-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.