Design and Syntheses of New Antibiotics Inspired by Nature's Quest for Iron in an Oxidative Climate.
Design and Syntheses of New Antibiotics Inspired by Nature's Quest for Iron in an Oxidative Climate.
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DOI：
10.1021/acs.accounts.1c00004
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发表时间：
2021-04-06
影响因子：
18.3
通讯作者：
Liu, Rui
中科院分区：
文献类型：
--
作者：
Miller, Marvin J.;Liu, Rui
该帐户描述了促进新抗生素发现的基础化学。具体而言，简单异羟肟酸衍生物的NH酸性促进了新型β-内酰胺（恶嗪和单环内酰胺）、限制细菌铁摄取的铁载体模拟物和细菌靶向铁霉素（铁载体-抗生素缀合物）的合成。对我们目前有限的抗生素支架的耐药性的发展已经造成了可怕的医疗状况。正如最近所说的，“如果你以前没有认真对待抗生素耐药性，现在是开始的好时机。英国政府委托的一个项目（https：//amr-review.org/）发布了对不久的将来全球抗生素耐药性的估计，其严重性和规模令人瞠目结舌：每年有1000万人死亡，至少有100万亿美元的国民生产总值牺牲。2020年COVID大流行证实传染病问题不再局限于局部地区，而是全球性的。许多经典的抗生素，特别是β-内酰胺，以前提供了经济的治疗方法，但是抗生素破坏性酶（即，β-内酰胺酶）、外排泵和细菌细胞壁通透性屏障已经使许多类型的细菌，特别是革兰氏阴性菌株产生耐药性。尽管如此，与其他疗法相比，公众的期望是任何新的抗生素必须便宜。这造成了市场限制，导致大多数主要制药公司放弃抗生素研究。要解决这一重大问题，还有许多工作要做。细菌螯合必需铁的迫切需要为新抗生素的开发提供了致命的弱点。虽然三价铁是极不溶性的，细菌需要微摩尔的细胞内浓度的生长和毒力。为此，它们生物合成铁载体（铁载体）并将其排泄到环境中，在那里它们以高亲和力结合铁。铁复合物被特定的外膜转运蛋白识别，一旦被积极内化，铁就被释放用于重要的过程。为了保存生物合成能量，一些细菌识别并利用竞争菌株产生的铁载体。作为无休止的生存斗争中的反革命，细菌还进化出了铁霉素，这是一种与弹头结合的铁载体，对流氓细菌是致命的。虽然现在没有一种用于治疗，但称为albomycins的天然铁霉素已用于临床，其他药物已被证明在动物感染模型中具有良好的耐受性和活性。在此，我们描述了合成具有上述一般结构的新抗生素和人工铁霉素（铁载体-连接体药物）的实用方法。利用基于分子识别的铁载体/铁霉素细菌同化过程，可以设计广谱和精确的窄谱（靶向）铁霉素，甚至重新使用旧的或更经典的抗生素。相关的微生物测定、体内动物感染研究以及最近FDA批准的头孢地罗酚都证明了它们的有效性。
This Account describes fundamental chemistry that promoted the discovery of new antibiotics. Specifically, the NH acidity of simple hydroxamic acid derivatives facilitated the syntheses of novel β-lactams (oxamazins and monobactams), siderophore mimics that limit bacterial iron uptake and bacterially targeted sideromycins (siderophore-antibiotic conjugates). The development of resistance to our current limited set of antibiotic scaffolds has created a dire medical situation. As recently stated, “if you weren’t taking antibiotic resistance seriously before, now would be a good time to start.” A project commissioned by the British government (https://amr-review.org/) has released estimates of the near-future global toll of antibiotic resistance that are jaw-dropping in their seriousness and scale: 10 million deaths per year and at least $100 trillion in sacrificed gross national product. The 2020 COVID pandemic confirmed that infectious disease problems are no longer localized but worldwide. Many classical antibiotics, especially β-lactams, previously provided economical cures, but the evolution of antibiotic destructive enzymes (i.e., β-lactamases), efflux pumps, and bacterial cell wall permeability barriers has made many types of bacteria, especially Gram-negative strains, resistant. Still, and in contrast to other therapies, the public expectation is that any new antibiotic must be inexpensive. This creates market limitations that have caused most major pharmaceutical companies to abandon antibiotic research. Much needs to be done to address this significant problem. The critical need for bacteria to sequester essential iron provides an Achilles’ heel for new antibiotic development. Although ferric iron is extremely insoluble, bacteria need micromolar intracellular concentrations for growth and virulence. To this end, they biosynthesize siderophores (Gr. iron bearer) and excrete them into their environment, where they bind iron with high affinity. The iron complexes are recognized by specific outer-membrane transporters, and once actively internalized, the iron is released for essential processes. To conserve biosynthetic energy, some bacteria recognize and utilize siderophores made by competing strains. As a counter-revolution in the never-ending fight for survival, bacteria have also evolved sideromycins, which are siderophores conjugated to warheads that are lethal to rogue bacteria. While none are now used therapeutically, natural sideromycins called albomycins have been used clinically, and others have been shown to be well tolerated and active in animal infection models. Herein we describe practical methods to synthesize new antibiotics and artificial sideromycins with the generalized structure shown above (siderophore-linker drug). Utilizing the molecular-recognition-based siderophore/sideromycin bacterial assimilation processes, it is possible to design both broad spectrum and exquisitely narrow spectrum (targeted) sideromycins and even repurpose older or more classical antibiotics. Relevant microbiological assays, in vivo animal infection studies, and the recent FDA approval of cefiderocol demonstrate their effectiveness.
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影响因子：
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通讯作者：
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通讯作者：
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通讯作者：
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