Ślusarz Rafał, Szulc Monika, Madaj Janusz
Faculty of Chemistry, University of Gdańsk, Wita Stwosza 63, 80-952 Gdańsk, Poland.
Faculty of Chemistry, University of Gdańsk, Wita Stwosza 63, 80-952 Gdańsk, Poland.
Carbohydr Res. 2014 May 7;389:154-64. doi: 10.1016/j.carres.2014.02.002. Epub 2014 Feb 12.
Proper understanding of the mechanisms of binding to Gram-positive bacteria cell wall layers-especially to the peptidoglycan (PG) layer, seems to be crucial for proper development of new drug candidates which are effective against these bacteria. In this work we have constructed two different models of the Gram-positive bacteria PG layer: the layered and the scaffold models. PG conformational changes during geometry optimization, models relaxation, and molecular dynamics were described and discussed. We have found that the border surface of both PG layer models differs from the surface located away from the edge of models and the chains formed by disaccharide units prefer helix-like conformation. This curling of PG chains significantly affects the shape of antibiotic-accessible surface and the process is thus crucial for new drug development. Glycopeptide antibiotics effective against Gram-positive bacteria, such as vancomycin and its semisynthetic derivatives-oritavancin and telavancin, bind to d-alanyl-d-alanine stem termini on the peptidoglycan precursors of the cell wall. This binding inhibits cross-linking between the peptides and subsequently prevents cell wall synthesis. In this study some of the aspects of conformational freedom of vancomycin and restrictions from the modifications of vancomycin structure introduced into oritavancin and telavancin and five other vancomycin derivatives (with addition of 2-acetamido-2-deoxy-β-d-galactopyranosylamine, 2-acetamido-2-deoxy-β-d-glucopyranosylamine, 1-amine-1-deoxy-d-glucitol, 2-amino-2-deoxy-d-galactitol, or 2-amino-2-deoxy-d-glucitol to the C-terminal amino acid group in the vancomycin) are presented and discussed. The resulting molecular dynamics trajectories, root mean square deviation changes of aglycon and saccharide moieties as well as a comparative study of possible interactions with cyclic and chain forms of modified groups have been carried out, measured, and analyzed. Energetically advantageous conformations show close similarity to the structures known from the experimental data, but the diversity of others suggest very high conformational freedom of all modeled antibiotics and vancomycin derivatives. Alditol derivatives move closer to the peptidoglycan chain more easily but they also form intramolecular interactions more frequently than their homologous cyclic forms. One of the proposed derivatives seems to be a promising agent which is efficient in treatment of infections caused by Gram-positive bacteria.
正确理解与革兰氏阳性菌细胞壁层（尤其是肽聚糖（PG）层）的结合机制，对于开发有效对抗这些细菌的新型候选药物似乎至关重要。在这项工作中，我们构建了革兰氏阳性菌PG层的两种不同模型：分层模型和支架模型。描述并讨论了PG在几何优化、模型弛豫和分子动力学过程中的构象变化。我们发现，两种PG层模型的边界表面与远离模型边缘的表面不同，并且由二糖单元形成的链更倾向于螺旋状构象。PG链的这种卷曲显著影响抗生素可及表面的形状，因此该过程对于新药开发至关重要。对革兰氏阳性菌有效的糖肽抗生素，如万古霉素及其半合成衍生物奥利万星和替考拉宁，与细胞壁肽聚糖前体上的d - 丙氨酰 - d - 丙氨酸茎端结合。这种结合抑制了肽之间的交联，从而阻止了细胞壁的合成。在本研究中，展示并讨论了万古霉素构象自由度的一些方面以及奥利万星和替考拉宁以及其他五种万古霉素衍生物（在万古霉素的C端氨基酸基团上添加2 - 乙酰氨基 - 2 - 脱氧 - β - d - 吡喃半乳糖胺、2 - 乙酰氨基 - 2 - 脱氧 - β - d - 吡喃葡萄糖胺、1 - 氨基 - 1 - 脱氧 - d - 葡萄糖醇、2 - 氨基 - 2 - 脱氧 - d - 半乳糖醇或2 - 氨基 - 2 - 脱氧 - d - 葡萄糖醇）中引入的万古霉素结构修饰所带来的限制。进行了所得分子动力学轨迹、苷元与糖部分的均方根偏差变化以及与修饰基团的环状和链状形式可能相互作用的比较研究，并进行了测量和分析。能量上有利的构象与实验数据中已知的结构非常相似，但其他构象的多样性表明所有建模的抗生素和万古霉素衍生物具有非常高的构象自由度。糖醇衍生物比其同源环状形式更容易靠近肽聚糖链，但它们也更频繁地形成分子内相互作用。其中一种提出的衍生物似乎是一种有前途的药物，对治疗革兰氏阳性菌引起的感染有效。
