Discovery of Unprecedented Arylation Coupling Cyclopeptide Inspires Natural Product-like Antitubercular Lead Compounds

Tuberculosis (TB) remains one of the world’s deadliest communicable diseases. Naturally derived antibiotics appear frequently in nature as collections of structurally similar compounds representing an adaptive evolutionary response to drug resistance development. Herein, we report an undescribed versicomycin (1), featuring an unprecedented post-nonribosomal peptide synthetase (NRPS) assembly line-modified skeleton, which was isolated from the marine-derived fungus. Gram-scale total synthesis of versicomycin (1) was accomplished using a hybrid synthesis strategy combining solid-phase chemistry, solution-phase cyclization, and chemical C–H bond functionalization. Inspired by this undescribed natural product (NP) skeleton, we efficiently developed a compound library comprising 89 natural product-like cycloheptapeptides (2–90) bearing aryl groups. Their antituberculosis activity, structure–activity relationships (SARs), and conformational effects along with in vitro and in vivo antibacterial effects were evaluated using Mycobacterium marinum. Remarkably, CHNQD-02353 (21), the most potent candidate, suppressed the proliferation of Mycobacterium tuberculosis H37Ra effectively with an MIC90 value of 0.25 μM, which is 300-fold lower than that of versicomycin (1). The in vitro study demonstrated that CHNQD-02353 exhibited biocompatibility and synergistic effects with major frontline drugs, indicating its broad clinical application potential. Further subcutaneous M. marinum infection study in mice revealed that CHNQD-02353 cleared bacteria effectively from lesions, demonstrating its in vivo anti-infective potential. These results show that our integrated research strategy has discovered a structurally untapped chemical class, representing a promising new area for antibiotic drug discovery.

结核病（TB）仍是全球致死性最高的传染病之一。天然衍生的抗生素在自然界中常以结构相似的化合物集合形式存在，这类化合物是针对耐药性产生的适应性进化应答产物。本研究报道了一种全新的疣孢霉素（versicomycin，1），其骨架具备前所未有的翻译后非核糖体肽合成酶（NRPS）装配线修饰特征，该化合物分离自海洋来源真菌。本研究采用固相化学、液相环化及化学C-H键官能化相结合的混合合成策略，完成了疣孢霉素（1）的克级规模全合成。受这一全新天然产物（NP）骨架的启发，我们高效构建了包含89种类天然产物环七肽（2–90）的化合物库，这类肽类均带有芳基取代基。以海分枝杆菌为模型，我们对该系列化合物的抗结核活性、构效关系（SARs）、构象效应以及体内外抗菌活性进行了评价。值得注意的是，活性最优的候选化合物CHNQD-02353（21）可有效抑制结核分枝杆菌H37Ra的增殖，其MIC90值为0.25 μM，仅为疣孢霉素（1）的1/300。体外研究表明，CHNQD-02353具备良好的生物相容性，且与主流一线抗结核药物具有协同作用，显示出广阔的临床应用潜力。进一步的小鼠皮下海分枝杆菌感染实验证实，CHNQD-02353可有效清除病灶内的细菌，验证了其体内抗感染潜力。上述结果表明，我们的整合研究策略发现了一类结构上未被开发的化学骨架，为抗生素药物研发开辟了极具前景的新方向。