Moreira Ryan, Yang Yi, Luo Youran, Gilmore Michael S, van der Donk Wilfred A
Department of Chemistry and Howard Hughes Medical Institute, University of Illinois at Urbana-Champaign Urbana IL 61822 USA
Departments of Ophthalmology and Microbiology, Harvard Medical School Boston MA 02144 USA.
RSC Chem Biol. 2024 Sep 4;5(10):1060-73. doi: 10.1039/d4cb00192c.
Here we describe bibacillin 1 - a two-component lantibiotic from . The peptides that comprise bibacillin 1 are modified by a class II lanthipeptide synthetase Bib1M producing two peptides with non-overlapping ring patterns that are reminiscent of cerecidin and the short component of the enterococcal cytolysin (CylL''), a virulence factor associated with human disease. Stereochemical analysis demonstrated that each component contains ll-methyllanthionine and dl-lanthionine. The mature bibacillin 1 peptides showed cooperative bactericidal activity against Gram-positive bacteria, including members of the ESKAPE pathogens, and weak hemolytic activity. Optimal ratio studies suggest that bibacillin 1 works best when the components are present in a 1 : 1 ratio, but near optimal activity was observed at ratios strongly favouring one component over the other, suggesting that the two peptides may have different but complementary targets. Mechanism of action studies suggest a lipid II-independent killing action distinguishing bibacillin 1 from two other two-component lantibiotics haloduracin and lacticin 3147. One of the two components of bibacillin 1 showed cross reactivity with the cytolysin regulatory system. These result support the involvement of bibacillin 1 in quorum sensing and raise questions about the impact of CylL''-like natural products on lanthipeptide expression in diverse bacterial communities.
在此，我们描述了双杆菌素1——一种来自……的双组分羊毛硫抗生素。构成双杆菌素1的肽由II类羊毛硫肽合成酶Bib1M修饰，产生两种具有不重叠环模式的肽，这让人联想到杀菌肽和肠球菌溶血素（CylL''）的短组分，CylL''是一种与人类疾病相关的毒力因子。立体化学分析表明，每个组分都含有ll-甲基羊毛硫氨酸和dl-羊毛硫氨酸。成熟的双杆菌素1肽对革兰氏阳性菌表现出协同杀菌活性，包括ESKAPE病原体成员，并且具有较弱的溶血活性。最佳比例研究表明，当组分以1∶1的比例存在时，双杆菌素1的效果最佳，但在强烈倾向于一种组分而非另一种组分的比例下也观察到了接近最佳的活性，这表明这两种肽可能具有不同但互补的靶点。作用机制研究表明，双杆菌素1具有不依赖脂质II的杀伤作用，这使其与另外两种双组分羊毛硫抗生素嗜盐菌素和乳酸乳球菌素3147有所区别。双杆菌素1的两个组分之一与溶血素调节系统表现出交叉反应。这些结果支持双杆菌素1参与群体感应，并引发了关于CylL''样天然产物对不同细菌群落中羊毛硫肽表达影响的问题。
