Conlon J Michael, Ahmed Eman, Condamine Eric
Department of Biochemistry, United Arab Emirates University, Al-Ain, UAE.
Chem Biol Drug Des. 2009 Nov;74(5):488-93. doi: 10.1111/j.1747-0285.2009.00882.x. Epub 2009 Sep 28.
Brevinin-2 related peptide (B2RP; GIWDTIKSMG(10)KVFAGKILQN(20)L.NH(2)), first isolated from skin secretions of the mink frog Lithobates septentrionalis, shows broad-spectrum antimicrobial activity but its therapeutic potential is limited by moderate hemolytic activity. The peptide adopts an alpha-helical conformation in a membrane-mimetic solvent but amphipathicity is low. Increasing amphipathicity together with hydrophobicity by the substitutions Lys(16)-->Leu and Lys(16)-->Ala increased hemolytic activity approximately fivefold without increasing antimicrobial potency. The substitution Leu(18)-->Lys increased both cationicity and amphipathicity but produced decreases in both antimicrobial potency and hemolytic activity. In contrast, increasing cationicity of B2RP without changing amphipathicity by the substitution Asp(4)-->Lys resulted in a fourfold increase in potency against Escherichia coli [minimal inhibitory concentration (MIC) = 6 microm) and twofold increases in potency against Staphylococcus aureus (MIC = 12.5 microm) and Candida albicans (MIC = 6 microm) without changing significantly hemolytic activity against human erythrocytes (LC(50) = 95 microm). The emergence of antibiotic-resistant strains of the Gram-negative bacterium Acinetobacter baumannii constitutes a serious risk to public health. B2RP (MIC = 3-6 microm) and [Lys(4)]B2RP (MIC = 1.5-3 microm) potently inhibited the growth of nosocomial isolates of multidrug-resistant Acinetobacter baumannii. Although the analogs [Lys(4), Lys(18)]B2RP and [Lys(4), Ala(16), Lys(18)]B2RP showed reduced potency against Staphylococcus aureus, they retained activity against Acinetobacter baumannii (MIC = 3-6 microm) and had very low hemolytic activity (LC(50) > 200 microm).
Brevinin-2相关肽（B2RP；GIWDTIKSMG(10)KVFAGKILQN(20)L.NH(2)）最初是从北美貂蛙（Lithobates septentrionalis）的皮肤分泌物中分离出来的，具有广谱抗菌活性，但其治疗潜力受到中等溶血活性的限制。该肽在模拟膜的溶剂中呈α-螺旋构象，但两亲性较低。通过将赖氨酸（Lys）(16)替换为亮氨酸（Leu）和将赖氨酸（Lys）(16)替换为丙氨酸（Ala）来增加两亲性和疏水性，溶血活性增加了约五倍，而抗菌效力并未提高。将亮氨酸（Leu）(18)替换为赖氨酸（Lys）增加了阳离子性和两亲性，但抗菌效力和溶血活性均降低。相比之下，通过将天冬氨酸（Asp）(4)替换为赖氨酸（Lys）来增加B2RP的阳离子性而不改变两亲性，对大肠杆菌的效力提高了四倍[最小抑菌浓度（MIC）=6微摩尔]，对金黄色葡萄球菌（MIC = 12.5微摩尔）和白色念珠菌（MIC = 6微摩尔）的效力提高了两倍，同时对人红细胞的溶血活性没有显著变化（半数溶血浓度（LC(50)）= 95微摩尔）。革兰氏阴性菌鲍曼不动杆菌的耐药菌株的出现对公众健康构成严重风险。B2RP（MIC = 3 - 6微摩尔）和[赖氨酸（Lys）(4)]B2RP（MIC = 1.5 - 3微摩尔）有效抑制了多药耐药鲍曼不动杆菌医院分离株的生长。尽管类似物[赖氨酸（Lys）(4)，赖氨酸（Lys）(18)]B2RP和[赖氨酸（Lys）(4)，丙氨酸（Ala）(16)，赖氨酸（Lys）(18)]B2RP对金黄色葡萄球菌的效力降低，但它们对鲍曼不动杆菌仍具有活性（MIC = 3 - 6微摩尔），并且溶血活性非常低（LC(50)> 200微摩尔）。
