The Multifaceted Antibacterial Mechanisms of the Pioneering Peptide Antibiotics Tyrocidine and Gramicidin S.
The Multifaceted Antibacterial Mechanisms of the Pioneering Peptide Antibiotics Tyrocidine and Gramicidin S.
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DOI：
10.1128/mbio.00802-18
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发表时间：
2018-10-09
期刊：
影响因子：
6.4
通讯作者：
Hamoen LW
中科院分区：
文献类型：
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作者：
Wenzel M;Rautenbach M;Vosloo JA;Siersma T;Aisenbrey CHM;Zaitseva E;Laubscher WE;van Rensburg W;Behrends JC;Bechinger B;Hamoen LW
环β折叠十肽，如短杆菌肽和短杆菌肽S，是最早应用于临床的抗生素之一。虽然它们已经使用了很长时间，但实际上对它们没有耐药性，这导致了对这类肽的新兴趣。短杆菌肽和短杆菌肽S都被认为会破坏细菌膜。然而，这些知识主要来自体外研究，关于这些历史悠久的抗生素如何杀死细菌的知识令人惊讶地很少。我们的研究结果揭示了β-折叠肽抗生素的抗菌机制，并解释了为什么它们仍然如此有效以及为什么对它们的耐药性如此之少。来自短杆菌肽组的环状β-折叠十肽和同源短杆菌肽S是第一种商业化使用的抗生素，但它们如何杀死细菌仍不清楚。我们使用细菌细胞学分析方法研究了它们的作用模式。酪肽形成确定的离子传导孔，诱导脂质相分离，并强烈降低膜流动性，导致广泛的外周和整合膜蛋白的离域。有趣的是，它们也会引起DNA损伤并干扰DNA结合蛋白。尽管短杆菌肽S与短杆菌肽具有50%的序列同一性，但短杆菌肽S仅引起轻度脂质分层，对膜流动性和渗透性的影响较小。短杆菌肽S使参与细胞分裂和细胞被膜合成的外周膜蛋白离域，但不影响完整的膜蛋白或DNA。我们的研究结果揭示了这些抗生素的多方面抗菌机制，并解释了为什么对它们的耐药性几乎不存在。
Cyclic β-sheet decapeptides, such as tyrocidines and gramicidin S, were among the first antibiotics in clinical application. Although they have been used for such a long time, there is virtually no resistance to them, which has led to a renewed interest in this peptide class. Both tyrocidines and gramicidin S are thought to disrupt the bacterial membrane. However, this knowledge is mainly derived from in vitro studies, and there is surprisingly little knowledge about how these long-established antibiotics kill bacteria. Our results shed new light on the antibacterial mechanism of β-sheet peptide antibiotics and explain why they are still so effective and why there is so little resistance to them. Cyclic β-sheet decapeptides from the tyrocidine group and the homologous gramicidin S were the first commercially used antibiotics, yet it remains unclear exactly how they kill bacteria. We investigated their mode of action using a bacterial cytological profiling approach. Tyrocidines form defined ion-conducting pores, induce lipid phase separation, and strongly reduce membrane fluidity, resulting in delocalization of a broad range of peripheral and integral membrane proteins. Interestingly, they also cause DNA damage and interfere with DNA-binding proteins. Despite sharing 50% sequence identity with tyrocidines, gramicidin S causes only mild lipid demixing with minor effects on membrane fluidity and permeability. Gramicidin S delocalizes peripheral membrane proteins involved in cell division and cell envelope synthesis but does not affect integral membrane proteins or DNA. Our results shed a new light on the multifaceted antibacterial mechanisms of these antibiotics and explain why resistance to them is virtually nonexistent.