Natural products with antibacterial activity are highly desired globally to combat against multidrug-resistant (MDR) bacteria. Antibacterial peptide (ABP), especially cyclic ABP (CABP), is one of the abundant classes. Most of them were isolated from microbes, demonstrating excellent bactericidal effects. With the improved proteolytic stability, CABPs are normally considered to have better druggability than linear peptides. However, most clinically-used CABP-based antibiotics, such as colistin, also face the challenges of drug resistance soon after they reached the market, urgently requiring the development of next-generation succedaneums. We present here a detail review on the novel naturally-occurring CABPs discovered in the past decade and some of them are under clinical trials, exhibiting anticipated application potential. According to their chemical structures, they were broadly classified into five groups, including (i) lactam/lactone-based CABPs, (ii) cyclic lipopeptides, (iii) glycopeptides, (iv) cyclic sulfur-rich peptides and (v) multiple-modified CABPs. Their chemical structures, antibacterial spectrums and proposed mechanisms are discussed. Moreover, engineered analogs of these novel CABPs are also summarized to preliminarily analyze their structure-activity relationship. This review aims to provide a global perspective on research and development of novel CABPs to highlight the effectiveness of derivatives design in identifying promising antibacterial agents. Further research efforts in this area are believed to play important roles in fighting against the multidrug-resistance crisis.

中文翻译：

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天然环状抗菌肽的挖掘及其结构优化策略


全球迫切需要具有抗菌活性的天然产品来对抗多重耐药（MDR）细菌。抗菌肽（ABP），尤其是环ABP（CABP），是数量丰富的一类。其中大部分是从微生物中分离出来的，表现出优异的杀菌效果。由于蛋白水解稳定性得到改善，CABP 通常被认为比线性肽具有更好的成药性。然而，大多数临床使用的基于CABP的抗生素，如粘菌素，在上市后不久也面临着耐药性的挑战，迫切需要开发下一代替代药物。我们在此对过去十年中发现的新型天然存在的 CABP 进行详细回顾，其中一些正在进行临床试验，表现出预期的应用潜力。根据其化学结构，它们大致分为五类，包括（i）基于内酰胺/内酯的CABP，（ii）环状脂肽，（iii）糖肽，（iv）环状富硫肽和（v）多重肽修改过的 CABP。讨论了它们的化学结构、抗菌谱和拟议的机制。此外，还总结了这些新型CABP的工程类似物，以初步分析它们的构效关系。本综述旨在为新型 CABP 的研究和开发提供全球视角，以强调衍生物设计在识别有前途的抗菌药物方面的有效性。相信该领域的进一步研究工作将在对抗多重耐药性危机中发挥重要作用。