Antimicrobial resistance is a significant threat to public health systems worldwide, prompting immediate attention to develop new therapeutic agents with novel mechanisms of action. Recently, two new cationic non-ribosomal peptides (CNRPs), laterocidine and brevicidine, were discovered from Brevibacillus laterosporus through a global genome-mining approach. Both laterocidine and brevicidine exhibit potent antimicrobial activity toward Gram-negative bacteria, including difficult-to-treat Pseudonomas aeruginosa and colistin-resistant Escherichia coli, and a low risk of resistance development. Herein, we report the first total syntheses of laterocidine and brevicidine via an efficient and high-yielding combination of solid-phase synthesis and solution-phase macrolactamization. The crucial depsipeptide bond of the macrolactone rings of laterocidine and brevicidine was established on-resin between the side-chain hydroxy group of Thr⁹ with Alloc-Gly-OH or Alloc-Ser(tBu)–OH, respectively. A conserved glycine residue within the lactone macrocycle is exploited for the initial immobilization onto the hyper acid-labile 2-chlorotrityl chloride resin, subsequently enabling an efficient solution-phase macrocyclization to yield laterocidine and brevicidine in 36% and 10% overall yields, respectively (with respect to resin loading). A biological evaluation against both Gram-positive and Gram-negative bacteria demonstrated that synthetic laterocidine and brevicidine possessed a potent and selective antimicrobial activity toward Gram-negative bacteria, in accordance with the isolated compounds.

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阳离子抗菌肽洛特西定和布雷维西丁的总化学合成及生物学评价

抗菌素耐药性是对全球公共卫生系统的重大威胁，促使人们立即关注开发具有新作用机制的新治疗剂。最近，通过全球基因组挖掘方法从侧孢短芽孢杆菌中发现了两种新的阳离子非核糖体肽 (CNRPs)，即侧切霉素和短缩氨酸。洛氏菌素和短杆菌肽都对革兰氏阴性菌表现出有效的抗菌活性，包括难以治疗的铜绿假单胞菌和耐粘菌素的大肠杆菌，并且产生耐药性的风险很低。在此，我们报告了通过固相合成和溶液相大环内酰胺化的高效和高产组合首次全合成阿魏酸和短缩丙啶。在树脂上的 Thr ⁹侧链羟基与 Alloc-Gly-OH 或 Alloc-Ser（tBu)-OH，分别。内酯大环内保守的甘氨酸残基被用于初始固定在超酸不稳定的 2-氯三苯甲基氯树脂上，随后实现有效的溶液相大环化，分别以 36% 和 10% 的总产率产生横切花定和短缩丙啶（关于树脂负载）。对革兰氏阳性菌和革兰氏阴性菌的生物学评估表明，根据分离出的化合物，合成的洛氏菌素和短杆菌肽对革兰氏阴性菌具有有效的选择性抗菌活性。