Hermant Yann, Palpal-Latoc Dennise, Kovalenko Nadiia, Cameron Alan J, Brimble Margaret A, Harris Paul W R
School of Chemical Sciences, The University of Auckland, 23 Symonds Street and 3b Symonds Street, Auckland 1142, New Zealand.
School of Biological Sciences, The University of Auckland, 3b Symonds Street, Auckland 1142, New Zealand.
J Nat Prod. 2021 Aug 27;84(8):2165-2174. doi: 10.1021/acs.jnatprod.1c00222. Epub 2021 Aug 2.
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 through a global genome-mining approach. Both laterocidine and brevicidine exhibit potent antimicrobial activity toward Gram-negative bacteria, including difficult-to-treat and colistin-resistant , 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 Thr with Alloc-Gly-OH or Alloc-Ser(Bu)-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.
抗菌耐药性是全球公共卫生系统面临的重大威胁，促使人们立即关注开发具有新型作用机制的新型治疗药物。最近，通过全球基因组挖掘方法从[具体来源未给出]中发现了两种新的阳离子非核糖体肽（CNRPs），即laterocidine和brevicidine。Laterocidine和brevicidine对革兰氏阴性菌均表现出强大的抗菌活性，包括难以治疗的[具体细菌名称未给出]和耐黏菌素的[具体细菌名称未给出]，并且耐药性发展风险较低。在此，我们报告了通过固相合成和溶液相大环化的高效高产组合首次全合成laterocidine和brevicidine。Laterocidine和brevicidine大环内酯环的关键缩肽键分别在树脂上由Thr的侧链羟基与Alloc-Gly-OH或Alloc-Ser(Bu)-OH形成。利用内酯大环内保守的甘氨酸残基将其最初固定在对酸高度不稳定的2-氯三苯甲基氯树脂上，随后实现高效的溶液相大环化，分别以36%和10%的总收率（相对于树脂负载量）得到laterocidine和brevicidine。针对革兰氏阳性菌和革兰氏阴性菌的生物学评价表明，合成的laterocidine和brevicidine对革兰氏阴性菌具有强大且选择性的抗菌活性，与分离得到的化合物一致。
