Novel Des-Fatty Acyl-Polymyxin B Derivatives with Pseudomonas aeruginosa-Specific Antimicrobial Activity

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概要

• 論文の詳細を見る

• Polymyxin B (PMB) is a cationic cyclic decapeptide antibiotic with a fatty acyl (FA) modification at the α-amino group of Dab1 (Dab: L-α,γ-diaminobutyric acid). In this study, which is part of a series of PMB structure–activity relationship investigations focused on identifying clinically useful peptide antibiotics, we synthesized ten des-FA PMB derivatives whose N-terminal moieties were changed to basic or hydrophilic amino acids. The antimicrobial and lipopolysaccharide (LPS) binding activities of these synthetic analogs were tested. The analogs showed more potent antimicrobial activity against Pseudomonas aeruginosa (P. aeruginosa) compared with the PMB nonapeptide. In particular, [Ser2-Dap3]-PMB(2—10), Guanyl-[Thr2-Dab3]-PMB(2—10), Guanyl-[Dab1-Thr2-Dab3]-PMB(1—10), and Nα,γ-diguanyl-[Dap3]-PMB(3—10) had antimicrobial activity equivalent to PMB. In LPS binding assays, the displacement curves shifted in a manner proportional to the number of positive charges available to bind to Escherichia coli (E. coli) and P. aeruginosa. Furthermore, peptides with basic side chains were comparable to PMB in binding activity assays against E. coli and P. aeruginosa. The acute toxicities of the peptides were evaluated by intravenously administering the peptides to mice through the tail vein. The toxicities of [Ser2-Dap3]-PMB(2—10), [Dap3]-PMB(3—10), and [Ser3]-PMB(3—10) were lower that of PMB (LD50, 4.8 μmol/kg).

著者

• SATO Yuki

  Faculty of Agriculture, Niigata University

• Sato Y

  Faculty Of Pharmaceutical Sciences Hokuriku University

• UCHIDA Yoshiki

  Department of Food Science and Nutrition, Osaka Shoin Women's University

• SHINDO Mitsuno

  Department of Food Science and Nutrition, Osaka Shoin Women's University

• 佐倉 直樹

  北陸大・薬

• Sakura N

  Hokuriku Univ. Kanazawa Jpn

• Sakura Naoki

  北陸大学 薬 生物活性

• Sakura Naoki

  北陸大学 薬学部

• Shindo Mitsuno

  Department Of Food Science And Nutrition Osaka Shoin Women's University

• Uchida Yoshiki

  Department Of Applied Chemistry Faculty Of Engineering Osaka City University

• Sakura Naoki

  Shizuoka Cancer Center Research Institute

• Kato Ikuo

  Faculty of Pharmaceutical Sciences, Hokuriku University

• Shindo Mitsuno

  Department Of Health And Nutrition Osaka Shoin Women's University

• Sato Yuki

  Faculty Of Agriculture Niigata University

• SHINDO Mitsuno

  Department of Health and Nutrition, Osaka Shoin Women's University

• Sato Yuki

  Faculty of Pharmaceutical Sciences, Hokuriku University

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