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

Sato Yuki, Shindo Mitsuno, Sakura Naoki, Uchida Yoshiki, Kato Ikuo

doi:10.1248/cpb.59.597

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 N^α,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).

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

この論文をさがす

抄録

収録刊行物

被引用文献 (1)*注記

参考文献 (23)*注記

キーワード

詳細情報詳細情報について

書き出し

問題の指摘

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

この論文をさがす

抄録

収録刊行物

被引用文献 (1)*注記

参考文献 (23)*注記

キーワード

詳細情報 詳細情報について

書き出し

問題の指摘

参加プロジェクトリスト

詳細情報詳細情報について