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[多环糖肽类新一代抗生素的创制史]

[History of the Creation of a New Generation of Antibiotics of the Group of Polycyclic Glycopeptides].

作者信息

Olsufyeva E N

机构信息

Gause Institute of New Antibiotics, Moscow, 119021 Russia.

出版信息

Mol Biol (Mosk). 2024 Nov-Dec;58(6):862-886.

Abstract

Increased resistance to polycyclic glycopeptide antibiotics has become a serious problem for chemotherapy of infections caused by resistant Gram-positive bacteria. Chemical modification of known natural antibiotics is the main direction in the creation of the next generation of anti-infective drugs. Over the past two decades, a series of hydrophobic glycopeptide analogues active against resistant strains of Gram-positive bacteria have been developed, three of which - oritavancin, telavancin, and dalbavancin - were approved by the US Food and Drug Administration (FDA) in 2013-2014 for the treatment of infections caused by sensitive and resistant strains of staphylococci and enterococci. It has been established that hydrophobic derivatives of glycopeptides can act on resistant strains of bacteria by a mechanism that does not allow binding to the modified target of resistant bacteria. Understanding the mechanism of action of natural and modified glycopeptides is considered as the basis for the rational design of compounds with valuable properties to achieve fundamental results. The possibility of using semi-synthetic glycopeptide analogues in the fight against viral infections caused by enveloped viruses is also considered. This review outlines the main ways of chemical design in creating a new generation of glycopeptide antibiotics that overcome resistance to Gram-positive pathogens and the mechanisms of their action.

摘要

对多环糖肽类抗生素耐药性的增加已成为耐药革兰氏阳性菌所致感染化疗的一个严重问题。对已知天然抗生素进行化学修饰是研发下一代抗感染药物的主要方向。在过去二十年中,已开发出一系列对革兰氏阳性菌耐药菌株有活性的疏水糖肽类似物,其中三种——奥利万星、特拉万星和达巴万星——于2013 - 2014年被美国食品药品监督管理局(FDA)批准用于治疗由敏感和耐药葡萄球菌及肠球菌菌株引起的感染。已证实糖肽的疏水衍生物可通过一种不允许与耐药菌修饰靶点结合的机制作用于耐药菌株。理解天然和修饰糖肽的作用机制被视为合理设计具有宝贵特性的化合物以取得根本性成果的基础。还考虑了使用半合成糖肽类似物对抗包膜病毒引起的病毒感染的可能性。本综述概述了在研发新一代克服对革兰氏阳性病原体耐药性的糖肽抗生素过程中的主要化学设计方法及其作用机制。

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