The Role of Iron and Siderophores in Infection, and the Development of Siderophore Antibiotics
The Role of Iron and Siderophores in Infection, and the Development of Siderophore Antibiotics
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DOI：
10.1093/cid/ciz825
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发表时间：
2019-12-01
影响因子：
11.8
通讯作者：
Page, Malcom G. P.
中科院分区：
文献类型：
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作者：
Page, Malcom G. P.
铁是细菌生长、复制和新陈代谢所必需的营养物质。人类储存的铁与各种蛋白质结合，如血红蛋白、结合珠蛋白、转铁蛋白、铁蛋白和乳铁蛋白，限制了致病菌对游离铁的可获得性。然而，细菌已经开发出各种机制来隔离或清除宿主环境中的铁。铁可以通过由细菌小分子铁载体、外膜铁载体受体、连接外膜和内膜的TonB-ExbBD能量转导蛋白和内膜转运蛋白组成的主动转运系统来吸收。一些细菌还表达宿主铁结合蛋白的外膜受体，并直接从这些受体中提取铁以供吸收。最终，铁被获取并运输到细菌细胞质中。铁载体是几乎所有细菌物种产生和释放的小分子，并根据其铁螯合基团的化学性质(即邻苯二酚、羟基甲酸盐、α-羟基羧酸盐或混合类型)进行分类。利用这种铁转运系统的铁载体结合抗生素正在开发中，用于治疗由革兰氏阴性细菌引起的感染。尽管显示出对致病性多药耐药细菌的高体外效力，但由于暴露期间明显的适应性耐药，缺乏一致的体内疗效，或宿主出现副作用，几个候选菌株的进一步开发已停止。然而，结构优化的头孢地洛已经取得进展，并已在1至3期临床试验中进行研究。本文讨论了铁摄取的机制，以及与铁载体类抗生素的设计和使用相关的挑战。
Iron is an essential nutrient for bacterial growth, replication, and metabolism. Humans store iron bound to various proteins such as hemoglobin, haptoglobin, transferrin, ferritin, and lactoferrin, limiting the availability of free iron for pathogenic bacteria. However, bacteria have developed various mechanisms to sequester or scavenge iron from the host environment. Iron can be taken up by means of active transport systems that consist of bacterial small molecule siderophores, outer membrane siderophore receptors, the TonB-ExbBD energy-transducing proteins coupling the outer and the inner membranes, and inner membrane transporters. Some bacteria also express outer membrane receptors for iron-binding proteins of the host and extract iron directly from these for uptake. Ultimately, iron is acquired and transported into the bacterial cytoplasm. The siderophores are small molecules produced and released by nearly all bacterial species and are classified according to the chemical nature of their iron-chelating group (ie, catechol, hydroxamate, alpha-hydroxyl-carboxylate, or mixed types). Siderophore-conjugated antibiotics that exploit such iron-transport systems are under development for the treatment of infections caused by gram-negative bacteria. Despite demonstrating high in vitro potency against pathogenic multidrug-resistant bacteria, further development of several candidates had stopped due to apparent adaptive resistance during exposure, lack of consistent in vivo efficacy, or emergence of side effects in the host. However, cefiderocol, with an optimized structure, has advanced and has been investigated in phase 1 to 3 clinical trials. This article discusses the mechanisms implicated in iron uptake and the challenges associated with the design and utilization of siderophore-mimicking antibiotics.