Department of Chemistry, Wesleyan University, Middletown, CT 06459, USA.
Int J Mol Sci. 2017 Oct 27;18(11):2256. doi: 10.3390/ijms18112256.
Bacterial antibiotic resistance is a rapidly expanding problem in the world today. Functionalization of the outer membrane of Gram-negative bacteria provides protection from extracellular antimicrobials, and serves as an innate resistance mechanism. Lipopolysaccharides (LPS) are a major cell-surface component of Gram-negative bacteria that contribute to protecting the bacterium from extracellular threats. LPS is biosynthesized by the sequential addition of sugar moieties by a number of glycosyltransferases (GTs). Heptosyltransferases catalyze the addition of multiple heptose sugars to form the core region of LPS; there are at most four heptosyltransferases found in all Gram-negative bacteria. The most studied of the four is HepI. Cells deficient in HepI display a truncated LPS on their cell surface, causing them to be more susceptible to hydrophobic antibiotics. HepI-IV are all structurally similar members of the GT-B structural family, a class of enzymes that have been found to be highly dynamic. Understanding conformational changes of heptosyltransferases are important to efficiently inhibiting them, but also contributing to the understanding of all GT-B enzymes. Finding new and smarter methods to inhibit bacterial growth is crucial, and the Heptosyltransferases may provide an important model for how to inhibit many GT-B enzymes.
细菌对抗生素的耐药性是当今世界一个迅速扩大的问题。革兰氏阴性菌外膜的功能化提供了对抗细胞外抗菌药物的保护，是一种先天的耐药机制。脂多糖（LPS）是革兰氏阴性菌的主要细胞表面成分，有助于保护细菌免受细胞外威胁。LPS 是由一系列糖基转移酶（GT）通过顺序添加糖基而生物合成的。己糖基转移酶催化将多个己糖添加到 LPS 的核心区域；所有革兰氏阴性菌中最多发现有四个己糖基转移酶。这四个中研究最多的是 HepI。缺乏 HepI 的细胞在其细胞表面显示出截短的 LPS，使它们更容易受到疏水性抗生素的影响。HepI-IV 都是 GT-B 结构家族的结构相似成员，该酶类已被发现具有高度动态性。了解己糖基转移酶的构象变化对于有效抑制它们很重要，但也有助于理解所有 GT-B 酶。寻找新的、更智能的方法来抑制细菌生长至关重要，而己糖基转移酶可能为如何抑制许多 GT-B 酶提供了一个重要的模型。
