Novel Des-Fatty Acyl-Polymyxin B Derivatives with Pseudomonas aeruginosa-Specific Antimicrobial Activity
作者:Yuki Sato、Mitsuno Shindo、Naoki Sakura、Yoshiki Uchida、Ikuo Kato
DOI:10.1248/cpb.59.597
日期:——
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).
多粘菌素 B (PMB) 是一种阳离子环状十肽抗生素,在 Dab1 的 α-氨基上进行了脂肪酰基 (FA) 修饰(Dab:L-α,γ-二氨基丁酸)。在这项研究中,这是一系列 PMB 结构-活性关系研究的一部分,重点是鉴定临床上有用的肽抗生素,我们合成了十种 des-FA PMB 衍生物,其 N 末端部分被改为碱性或亲水氨基酸。测试了这些合成类似物的抗菌和脂多糖(LPS)结合活性。与 PMB 九肽相比,这些类似物对铜绿假单胞菌 (P. aeruginosa) 显示出更有效的抗菌活性。特别地,[Ser2-Dap3]-PMB(2-10)、脒基-[Thr2-Dab3]-PMB(2-10)、脒基-[Dab1-Thr2-Dab3]-PMB(1-10)和Na ,γ-二鸟苷基-[Dap3]-PMB(3—10)具有与PMB相当的抗菌活性。在 LPS 结合测定中,位移曲线以与可结合大肠杆菌 (E. coli) 和铜绿假单胞菌的正电荷数量成比例的方式移动。此外,在针对大肠杆菌和铜绿假单胞菌的结合活性测定中,具有碱性侧链的肽与 PMB 相当。通过尾静脉向小鼠静脉注射肽来评估肽的急性毒性。 [Ser2-Dap3]-PMB(2—10)、[Dap3]-PMB(3—10)和[Ser3]-PMB(3—10)的毒性低于PMB(LD50,4.8 μmol/kg) )。