Mor A, Hani K, Nicolas P
Laboratoire de Bioactivation des Peptides, Institut Jacques Monod, Université Paris 7, France.
J Biol Chem. 1994 Dec 16;269(50):31635-41.
The physiological significance of the occurrence of sequence similar antimicrobial peptides in frog skin, as the bombinins in Bombina, the magainins in Xenopus, and the dermaseptins in Phyllomedusa, is a major unanswered question. Dermaseptins s1, s2, s3, s4, and s5, a family of cationic (lysine-rich), amphipathic antifungal peptides of 28-34 residues were thus synthesized, purified to homogeneity, and evaluated for their growth-inhibition activity in vitro against various pathogenic microorganisms. Although all five of these peptides shared a similar spectrum of lytic activity against the filamentous fungi that are responsible for opportunistic lethal infections that follow the immunodeficiency syndrome or the use of immunosuppressive agents, they exhibited marked differences in their potencies to arrest the growth of Gram-positive and Gram-negative pathogenic bacteria and yeasts. Likewise, whereas dermaseptins s1 and s5 were devoid of hemolytic activity, dermaseptin s4 caused lysis of erythrocytes at micromolar concentrations. The dermaseptins exhibited dramatic synergy of action upon combination, resulting in some cases in a 100-fold increase in antibiotic activity of the mixture over the activity of the peptides separately. Shortening the peptide chain of dermaseptin s3 to dermaseptin s3-(1-16)-NH2 did not affect the antimicrobial potency of the peptide. Further reduction of the chain length yielded peptide derivatives gradually showing reduced activity. Surprisingly, however, analogs of dermaseptin s3 as shorter as 10-12 residues in length remained fully active against Enterococcus faecalis, Cryptococcus neoformans, and against Aeromonas caviae, the causal agent of red-leg disease in amphibians. Overall, these results suggest that, despite 40% sequence similarities, the dermaseptins have distinct spectra of anti-microbial activity and may act in concert to circumvent host invasion by providing frogs with a better shielding against a broad array of microorganisms. They also demonstrate the potential usefulness of short analogs of these peptides as potential candidates for biorational design of germicides.
蛙类皮肤中出现序列相似的抗菌肽，如铃蟾属中的铃蟾肽、非洲爪蟾属中的爪蟾抗菌肽以及叶泡蛙属中的皮防御素，其生理意义仍是一个主要的未解之谜。因此，合成了皮防御素s1、s2、s3、s4和s5，这是一族由28 - 34个残基组成的阳离子型（富含赖氨酸）两亲性抗真菌肽，将其纯化至同质，并评估其体外对各种致病微生物的生长抑制活性。尽管这五种肽对导致免疫缺陷综合征或使用免疫抑制剂后发生的机会性致命感染的丝状真菌具有相似的裂解活性谱，但它们在抑制革兰氏阳性和革兰氏阴性致病细菌及酵母生长的效力上表现出显著差异。同样，皮防御素s1和s5没有溶血活性，而皮防御素s4在微摩尔浓度下会导致红细胞裂解。皮防御素在组合时表现出显著的协同作用，在某些情况下，混合物的抗生素活性比单独的肽活性增加了100倍。将皮防御素s3的肽链缩短为皮防御素s3-(1 - 16)-NH2并不影响该肽的抗菌效力。进一步缩短链长会使肽衍生物的活性逐渐降低。然而，令人惊讶的是，长度短至10 - 12个残基的皮防御素s3类似物对粪肠球菌、新型隐球菌以及两栖类红腿病的病原体嗜水气单胞菌仍保持完全活性。总体而言，这些结果表明，尽管序列相似性为40%，但皮防御素具有不同的抗菌活性谱，并且可能协同作用，通过为青蛙提供更好的防护以抵御多种微生物来规避宿主感染。它们还证明了这些肽的短类似物作为杀菌剂生物合理设计的潜在候选物的潜在用途。
