Journal
ACS INFECTIOUS DISEASES
Volume 5, Issue 10, Pages 1645-1656Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsinfecdis.9b00217
Keywords
polymyxin; antimicrobial resistance; multidrug-resistant bacteria; nephrotoxicity; antibacterials; Gram-negative
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Funding
- Innovate UK under the Biomedical Catalyst scheme [101357]
- US Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services [HHSN272201500014C]
- Innovate UK [101357] Funding Source: UKRI
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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 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.
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