Discovery, synthesis, and optimization of teixobactin, a novel antibiotic without detectable bacterial resistance,Journal of Peptide Science

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Discovery, synthesis, and optimization of teixobactin, a novel antibiotic without detectable bacterial resistance
Journal of Peptide Science ( IF 1.8 ) Pub Date : 2022-05-24 , DOI: 10.1002/psc.3428
Yun-Kun Qi _{1,

2,

3} , Xiaowen Tang ₁ , Ning-Ning Wei ₂ , Cheng-Jian Pang ₄ , Shan-Shan Du ₃ , KeWei Wang _{1,

2}

Affiliation

Discovering new antibiotics with novel chemical scaffolds and antibacterial mechanisms presents a challenge for medicinal scientists worldwide as the ever-increasing bacterial resistance poses a serious threat to human health. A new cyclic peptide-based antibiotic termed teixobactin was discovered from a screen of uncultured soil bacteria through iChip technology in 2015. Teixobactin exhibits excellent antibacterial activity against all the tested gram-positive pathogens and Mycobacterium tuberculosis, including drug-resistant strains. Given that teixobactin targets the highly conserved lipid II and lipid III, which induces the simultaneous inhibition of both peptidoglycan and teichoic acid synthesis, the emergence of resistance is considered to be rather difficult. The novel structure, potent antibacterial activity, and highly conservative targets make teixobactin a promising lead compound for further antibiotic development. This review provides a comprehensive treatise on the advances of teixobactin in the areas of discovery processes, antibacterial activity, mechanisms of action, chemical synthesis, and structural optimizations. The synthetic methods for the key building block l-allo-End, natural teixobactin, representative teixobactin analogs, as well as the structure–activity relationship studies will be highlighted and discussed in details. Finally, some insights into new trends for the generation of novel teixobactin analogs and tips for future work and directions will be commented.

中文翻译：

teixobactin 的发现、合成和优化，一种没有可检测到细菌耐药性的新型抗生素

发现具有新型化学支架和抗菌机制的新型抗生素对全世界的医学科学家提出了挑战，因为不断增加的细菌耐药性对人类健康构成了严重威胁。2015 年，通过 iChip 技术从未经培养的土壤细菌筛选中发现了一种名为 teixobactin 的新型环肽类抗生素。 Teixobactin 对所有测试的革兰氏阳性病原体和结核分枝杆菌均表现出优异的抗菌活性，包括耐药菌株。鉴于 teixobactin 靶向高度保守的脂质 II 和脂质 III，这会同时抑制肽聚糖和磷壁酸的合成，因此耐药性的出现被认为是相当困难的。新颖的结构、有效的抗菌活性和高度保守的靶点使 teixobactin 成为进一步开发抗生素的有希望的先导化合物。这篇综述对 teixobactin 在发现过程、抗菌活性、作用机制、化学合成和结构优化等领域的进展进行了全面的论述。关键构件l - allo的合成方法-最后，将重点介绍和详细讨论天然 teixobactin、代表性 teixobactin 类似物以及构效关系研究。最后，将对产生新型 teixobactin 类似物的新趋势的一些见解以及未来工作和方向的提示进行评论。

更新日期：2022-05-24

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