Anti-antimicrobial peptides: folding-mediated host defense antagonists.
Anti-antimicrobial peptides: folding-mediated host defense antagonists.
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DOI：
10.1074/jbc.m113.459560
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发表时间：
2013-07-12
期刊：
影响因子：
--
通讯作者：
Ryadnov MG
中科院分区：
文献类型：
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作者：
Ryan L;Lamarre B;Diu T;Ravi J;Judge PJ;Temple A;Carr M;Cerasoli E;Su B;Jenkinson HF;Martyna G;Crain J;Watts A;Ryadnov MG
背景：天然抗菌肽(AMP)序列的直接拮抗剂尚不清楚。结果：互补的拮抗序列可以与AMP共折叠成功能惰性的组装。结论：拮抗剂具有抗AMP的作用。意义：这些发现为抗AMP反应提供了分子基础，并可能对抗菌素耐药性产生影响。抗菌肽或宿主防御肽是存在于所有多细胞生物体中的天然免疫调节剂。它们中的许多折叠成膜结合的α-螺旋，并通过在微生物中引起细胞壁破坏来发挥作用。在这里，我们探讨了抗菌肽与从头设计的拮抗剂抗菌肽之间的互补螺旋相互作用介导抗菌拮抗作用的可能性和功能意义。使用天然螺旋家族的序列，如天冬氨酸、天蚕素和麦芽菌素，我们证明了设计的拮抗剂可以与抗菌肽共折叠成功能惰性的螺旋低聚物。通过手性和固态核磁共振光谱、显微镜、生物测定和分子动力学模拟相结合的方法，在溶液、膜环境和细菌培养中研究了所得到的组装体的性质和功能。这些发现为抗菌素反应提供了分子基础，并可能对抗菌素耐药性产生影响。
Background: Direct antagonists of native antimicrobial peptide (AMP) sequences are unknown. Results: Complementary antagonistic sequences can co-fold with AMPs into functionally inert assemblies. Conclusion: Antagonists act as anti-AMPs. Significance: The findings offer a molecular rationale for anti-AMP responses with potential implications for antimicrobial resistance. Antimicrobial or host defense peptides are innate immune regulators found in all multicellular organisms. Many of them fold into membrane-bound α-helices and function by causing cell wall disruption in microorganisms. Herein we probe the possibility and functional implications of antimicrobial antagonism mediated by complementary coiled-coil interactions between antimicrobial peptides and de novo designed antagonists: anti-antimicrobial peptides. Using sequences from native helical families such as cathelicidins, cecropins, and magainins we demonstrate that designed antagonists can co-fold with antimicrobial peptides into functionally inert helical oligomers. The properties and function of the resulting assemblies were studied in solution, membrane environments, and in bacterial culture by a combination of chiroptical and solid-state NMR spectroscopies, microscopy, bioassays, and molecular dynamics simulations. The findings offer a molecular rationale for anti-antimicrobial responses with potential implications for antimicrobial resistance.