Abstract：
Di-branched and tetra-branched versions of a previously reported analogue of the lipopeptide battacin were successfully synthesised using thiol-maleimide click and 1, 2, 3-triazole click chemistry. Antimicrobial studies against drug resistant clinical isolates of Escherichia coli (ESBL E. coli Ctx-M14), Pseudomonas aeruginosa (P. aeruginosa Q502), and Methicillin resistant Staphylococcus aureus (MRSA ATCC 33593), as well as clinically isolated Acinetobacter baumannii (A. baumannii ATCC 19606), and P. aeruginosa (ATCC 27853), revealed that the dendrimeric peptides have antimicrobial activity in the low micromolar range (0.5 -- 4 μM) which was 10 times more potent than the monomer peptides. Under high salt concentrations (150 mM NaCl, 2 mM MgCl2, and 2.5 mM CaCl2) the di-branched lipopeptides retained their antimicrobial activity while the monomer peptides were not active (>100 μM). The di-branched triazole click lipopeptide, Peptide 12, was membrane lytic, showed faster killing kinetics, and exhibited antibiofilm activity against A. baumannii and MRSA and eradicated > 85 % preformed biofilms at low micromolar concentrations. The di-branched analogues were > 30-fold potent than the monomers against Candida albicans. Peptide 12 was not haemolytic (HC10 = 932.12 μM) and showed up to 40-fold higher selectivity against bacteria and fungi than the monomer peptide. Peptide 12 exhibited strong proteolytic stability (>80 % not degraded) in rat serum over 24 h whereas > 95 % of the thiol-maleimide analogue (Peptide 10) was degraded. The tetra-branched peptides showed comparable antibacterial potency to the di-branched analogues. These findings indicate that dual branching using triazole click chemistry is a promising strategy to improve the antimicrobial activity and proteolytic stability of battacin based lipopeptides. The information gathered can be used to build effective antimicrobial dendrimeric peptides as new peptide antibiotics.
摘要：
使用硫醇-马来酰亚胺点击和1,2,3-三唑点击化学成功合成了先前报道的脂肽氮芥类似物的二支链和四支链形式。抗微生物研究对耐药大肠杆菌临床分离株（ESBL大肠杆菌Ctx-M14），铜绿假单胞菌(P.铜绿假Q502)，和耐甲氧西林金黄色葡萄球菌（MRSAATCC33593），以及临床分离的鲍曼不动杆菌（A.鲍曼不动ATCC19606)，和铜绿假单胞菌（ATCC27853），揭示了树枝状肽在低微摩尔范围（0.5-4μM）具有抗微生物活性，其效力是单体肽的10倍。在高盐浓度(150mMNaCl，2mMMgCl2和2.5mMCaCl2），二分支脂肽保留了其抗微生物活性，而单体肽则没有活性（>100μM）。二支链三唑点击脂肽，肽12，是膜裂解，显示出更快的杀伤动力学，并表现出抗鲍曼不动杆菌和MRSA的抗生物膜活性，并在低微摩尔浓度下根除>85％的预制生物膜。双支链类似物对白色念珠菌的效力比单体多30倍。肽12不是溶血性的(HC10=932.12μM),并且对细菌和真菌的选择性比单体肽高40倍。肽12在大鼠血清中在24小时内表现出强的蛋白水解稳定性(>80%未降解),而>95%的硫醇-马来酰亚胺类似物(肽10)被降解。四分支肽显示与二分支类似物相当的抗菌效力。这些发现表明,使用三唑点击化学的双重分支是改善基于battacin的脂肽的抗微生物活性和蛋白水解稳定性的有希望的策略。收集的信息可用于构建有效的抗微生物树枝状肽作为新的肽抗生素。
