Synthesis and Evaluation of Polymyxins Bearing Reductively Labile Disulfide-Linked Lipids
| Autor: | Slingerland, Cornelis J., Wesseling, Charlotte M. J., Innocenti, Paolo, Westphal, Koen G. C., Masereeuw, Rosalinde, Martin, Nathaniel I., Afd Chemical Biology and Drug Discovery, Afd Pharmacology, Chemical Biology and Drug Discovery, Pharmacology |
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| Přispěvatelé: | Afd Chemical Biology and Drug Discovery, Afd Pharmacology, Chemical Biology and Drug Discovery, Pharmacology |
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: | |
| Zdroj: | Journal of Medicinal Chemistry. AMER CHEMICAL SOC Journal of Medicinal Chemistry Journal of Medicinal Chemistry, 65(23), 15878-15892. American Chemical Society (ACS) Journal of Medicinal Chemistry, 65(23). American Chemical Society : Division of Carbohydrate Chemistry |
| ISSN: | 0022-2623 |
| Popis: | Polymyxins are a class of lipopeptide anti-infective agents with potent and specific activity against Gram-negative bacteria. While toxicity concerns associated with polymyxin B and E (colistin) have historically limited their clinical application, today they are increasingly used as last-resort antibiotics given the rise of multidrug-resistant Gram-negative pathogens. The adverse side effects of polymyxins are well known, particularly as related to their nephrotoxicity. Here, we describe the synthesis and evaluation of a novel series of polymyxin analogues, aimed at reducing their nephrotoxic effects. Using a semisynthetic approach, we explored modifications of the exocyclic part of the polymyxin scaffold, namely, the terminal amino acid and lipophilic tail. By incorporating a reductively labile disulfide linkage in the lipid tail, we obtained novel polymyxins that exhibit potent antibacterial activity on par with polymyxin B but with reduced toxicity toward human renal proximal tubular epithelial cells. |
| Databáze: | OpenAIRE |
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