Activity of cecropin A-melittin hybrid peptides against colistin-resistant clinical strains of Acinetobacter baumannii:: Molecular basis for the differential mechanisms of action
Activity of cecropin A-melittin hybrid peptides against colistin-resistant clinical strains of Acinetobacter baumannii:: Molecular basis for the differential mechanisms of action
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DOI：
10.1128/aac.50.4.1251-1256.2006
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发表时间：
2006-04-01
影响因子：
4.9
通讯作者：
Rivas, L
中科院分区：
文献类型：
--
作者：
Saugar, JM;Rodríguez-Hernández, MJ;Rivas, L
鲍曼不动杆菌已成功地对所有常见抗生素产生了耐药性，包括粘菌素（多粘菌素E），这是针对该病原体的最后一种普遍有效的药物。抗粘菌素A.鲍曼不动杆菌菌株可能产生令人担忧的临床情况。在以前的工作中，我们报道了多粘菌素B（PX B）和天蚕素A-蜂毒肽（CA-M）杂合肽CA（1-8）M（1- 1 - 8）（KWKLFKKIGIGAVLKVLTTGLPALIS-NH 2）对粘菌素敏感菌株致死机制的差异（J. M. Saugar，T.阿拉尔孔，S. Lopez-Hernandez，M. Lopez-Brea，D. Andreu和L.里瓦斯，抗菌剂。探员Chemother 46：875-878，2002）。我们现在证明CA（1-8）M（1- 1 - 8）和三种短类似物，即CA（1-7）M（2-9）（KWICLFKKIGAVLKVL-NH 2）、其N-α-辛酰基衍生物（Oct-KWKLFKKIGAVLKVL-NH 2）和CA（1-7）M（5-9）（KWKLLKKIGAVLKVL-NH 2）对两种粘菌素耐药临床菌株具有活性。在体外，对硫酸粘杆菌素的抗性靶向外膜，因为原生质球被给定的肽同等地裂解，而不管它们各自的粘杆菌素抗性水平如何。CA-M杂合体在从粘菌素抗性菌株而不是从粘菌素敏感菌株中置换脂多糖结合的丹磺酰-多粘菌素B方面比粘菌素更有效。无论菌株的电阻模式如何，观察到CA-M杂化物在内膜渗透方面的类似改进性能。这些结果支持CA-M肽的可能用途，并通过扩展具有类似特征的其他抗微生物肽，作为粘菌素耐药不动杆菌感染的替代化疗。
Acinetobacter baumannii has successfully developed resistance against all common antibiotics, including colistin (polymyxin E), the last universally active drug against this pathogen. The possible widespread distribution of colistin-resistant A. baumannii strains may create an alarming clinical situation. In a previous work, we reported differences in lethal mechanisms between polymyxin B (PXB) and the cecropin A-melittin (CA-M) hybrid peptide CA(1-8)M(1-18) (KWKLFKKIGIGAVLKVLTTGLPALIS-NH2) on colistin-susceptible strains (J. M. Saugar,T. Alarcon, S. Lopez-Hernandez, M. Lopez-Brea, D. Andreu, and L. Rivas, Antimicrob. Agents Chemother. 46:875-878, 2002). We now demonstrate that CA(1-8)M(1-18) and three short analogues, namely CA(1-7)M(2-9) (KWICLFKKIGAVLKVL-NH2), its N-alpha-octanoyl derivative (Oct-KWKLFKKIGAVLKVL-NH2), and CA(1-7)M(5-9) (KWKLLKKIGAVLKVL-NH2) are active against two colistin-resistant clinical strains. In vitro, resistance to colistin sulfate was targeted to the outer membrane, as spheroplasts were equally lysed by a given peptide, regardless of their respective level of colistin resistance. The CA-M hybrids were more efficient than colistin in displacing lipopolysaccharide-bound dansyl-polymyxin B from colistin-resistant but not from colistin-susceptible strains. Similar improved performance of the CA-M hybrids in permeation of the inner membrane was observed, regardless of the resistance pattern of the strain. These results argue in favor of a possible use of CA-M peptides, and by extension other antimicrobial peptides with similar features, as alternative chemotherapy in colistin-resistant Acinetobacter infections.