Targeting membrane-bound bacterial cell wall precursors: a tried and true antibiotic strategy in nature and the clinic.
Targeting membrane-bound bacterial cell wall precursors: a tried and true antibiotic strategy in nature and the clinic.
复制标题
靶向膜结合细菌细胞壁前体：自然界和临床中经过验证的真实抗生素策略。
DOI：
10.1039/d3cc01070h
复制
发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Buijs NP
中科院分区：
文献类型：
--
作者：
Buijs NP
自从弗莱明在近一个世纪前发现青霉素以来，人们发现了大量的天然抗生素，其中许多至今仍具有临床重要性。自然界中抗生素的结构多样性反映在它们选择性靶向和杀死细菌细胞的不同作用机制上。细菌构建和维持强大细胞壁的能力对于它们在各种条件下的强劲生长和生存至关重要。然而，维持细胞壁的需要也呈现出被许多天然抗生素利用的脆弱性。细菌细胞壁的生物合成既包括复杂的膜结合前体分子的构建，也包括它们随后通过专用酶的交联。有趣的是，许多天然抗生素的作用不是直接抑制与细胞壁生物合成相关的酶，而是通过与它们的膜结合底物紧密结合。这种底物隔离机制在抗生素领域之外相对罕见，大多数小分子药物发现项目旨在开发目标酶的抑制剂。在这篇专题文章中，我们为读者提供了一个独特的和不断增加的天然产物抗生素家族的概述，已知通过结合膜锚定的细菌细胞壁前体特异性功能。在此过程中，我们强调了我们自己对该领域的贡献，以及其他研究人员在探索针对细菌细胞壁前体的抗生素所提供的潜力方面所做的贡献。
Since Fleming's discovery of penicillin nearly a century ago, a bounty of natural product antibiotics have been discovered, many of which continue to be of clinical importance today. The structural diversity encountered among nature's repertoire of antibiotics is mirrored by the varying mechanisms of action by which they selectively target and kill bacterial cells. The ability for bacteria to construct and maintain a strong cell wall is essential for their robust growth and survival under a range of conditions. However, the need to maintain the cell wall also presents a vulnerability that is exploited by many natural antibiotics. Bacterial cell wall biosynthesis involves both the construction of complex membrane-bound precursor molecules and their subsequent crosslinking by dedicated enzymes. Interestingly, many naturally occurring antibiotics function not by directly inhibiting the enzymes associated with cell wall biosynthesis, but rather by binding tightly to their membrane-bound substrates. Such substrate sequestration mechanisms are comparatively rare outside of the antibiotics space with most small-molecule drug discovery programs instead aimed at developing inhibitors of target enzymes. In this feature article we provide the reader with an overview of the unique and ever increasing family of natural product antibiotics known to specifically function by binding to membrane-anchored bacterial cell wall precursors. In doing so, we highlight both our own contributions to the field as well as those made by other researchers engaged in exploring the potential offered by antibiotics that target bacterial cell wall precursors.