Carboxyl Analogue of Mutacin 1140, a Scaffold for Lead Antibacterial Discovery
Carboxyl Analogue of Mutacin 1140, a Scaffold for Lead Antibacterial Discovery
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DOI：
10.1128/aem.00668-17
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发表时间：
2017-07-01
影响因子：
4.4
通讯作者：
Smith, Leif
中科院分区：
文献类型：
--
作者：
Escano, Jerome;Ravichandran, Akshaya;Smith, Leif
突变蛋白1140属于羊毛硫抗生素的表皮素组。Epidermin类羊毛硫抗生素是核糖体合成和后修饰的抗生素，对革兰氏阳性菌具有强效活性。特别是，这类药物可有效靶向耐药肺炎链球菌、耐甲氧西林金黄色葡萄球菌（MRSA）、结核分枝杆菌和艰难梭菌。C-末端S-[（Z）-2-氨基乙烯基]-D-半胱氨酸（AviCys）残基衍生自参与羊毛硫氨酸环形成的末端半胱氨酸的脱羧。对突变蛋白1140的研究揭示了C-末端AviCys残基的结构重要性的新见解。突变蛋白1140的C-末端羧基类似物被工程化。用伯胺封端C-末端羧基恢复了生物活性，并提供了合成新类似物的新机会。C-末端荧光素标记的突变蛋白1140类似物将脂质II捕获到大的脂质II lantibiotic复合物中，类似于在体内观察到的lantibiotic nisin。突变蛋白1140的C-末端羧基类似物竞争性抑制天然突变蛋白1140和乳链菌肽的活性。C-末端羧基的存在阻止了大的脂质II lantibiotic复合物的形成，但并不阻止lantibiotic与脂质II的结合。重要性本研究讨论了C-末端S-[（Z）-2氨基乙烯基]-D-半胱氨酸（AviCys）残基对抗菌活性的重要性。我们已经了解到，翻译后修饰，使阿维半胱氨酸残基大概是重要的横向组装机制的活动，陷阱脂质II成一个大的复杂。这类羊毛硫抗生素的C-末端羧基类似物适合加入各种各样的底物。荧光素的加入使得能够在体内可视化表皮素类的羊毛硫抗生素的作用。这些结果是重要的，因为正如我们所证明的，AviCys残基的存在对于生物活性不是必需的，但更重要的是，羧基的去除是必需的。制备可修饰的C-末端羧基类似物的能力将促进可开发用于新应用的羊毛硫抗生素的表皮素类的新型类似物的合成。
Mutacin 1140 belongs to the epidermin group of lantibiotics. Epidermin class lantibiotics are ribosomally synthesized and posttranslationally modified antibiotics with potent activity against Gram-positive bacteria. In particular, this class is effective at targeting drug-resistant Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus (MRSA), Mycobacterium tuberculosis, and Clostridium difficile. A C-terminal S-[(Z)-2-aminovinyl]-D-cysteine (AviCys) residue is derived from a decarboxylation of a terminal cysteine that is involved in lanthionine ring formation. Studies on mutacin 1140 have revealed new insight into the structural importance of the C-terminal AviCys residue. A C-terminal carboxyl analogue of mutacin 1140 was engineered. Capping the C-terminal carboxyl group with a primary amine restores bioactivity and affords a novel opportunity to synthesize new analogues. A C-terminal fluorescein-labeled mutacin 1140 analogue traps lipid II into a large lipid II lantibiotic complex, similar to that observed in vivo for the lantibiotic nisin. A C-terminal carboxyl analogue of mutacin 1140 competitively inhibits the activity of native mutacin 1140 and nisin. The presence of a C-terminal carboxyl group prevents the formation of the large lipid II lantibiotic complexes but does not prevent the binding of the lantibiotic to lipid II.IMPORTANCE This study addressed the importance of the C-terminal S-[(Z)-2aminovinyl]- D-cysteine (AviCys) residue for antibacterial activity. We have learned that the posttranslational modification for making the AviCys residue is presumably important for the lateral assembly mechanism of activity that traps lipid II into a large complex. The C-terminal carboxyl analogue of this class of lantibiotics is agreeable to the addition of a wide variety of substrates. The addition of fluorescein enabled in vivo visualization of the epidermin class of lantibiotics in action. These results are significant because, as we demonstrate, the presence of the AviCys residue is not essential for bioactivity, but, more importantly, the removal of the carboxyl group is essential. The ability to make a C-terminal carboxyl analogue that is modifiable will facilitate the synthesis of novel analogues of the epidermin class of lantibiotics that can be developed for new applications.