Runze Sun, Di Zhao, Xuchang Yu, Fei Zhang, Ruixiang You, Xiaoxia Luo, Lei Li
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引用次数: 0
摘要
细菌膜中的甲萘醌(MK)是开发新型治疗药物的一个极具吸引力的靶点。挖掘革兰氏阴性细菌编码的尚未开发的化学多样性为发现更多的 MK 结合抗生素(MBAs)提供了机会。通过对 45 个未充分开发的革兰氏阴性菌属的 14,298 个测序基因组中生物信息学预测的线性非核糖体肽进行 MK 结合主题搜索,我们在此利用结构预测指导下的化学合成发现了一个新型 MBA 结构家族,包括 silvmeb 和 pseudomeb。这两种 MBA 都能通过 MK 依赖性膜去极化快速溶菌,从而对一系列革兰氏阳性病原体产生强效活性。此外,在小鼠腹膜炎-败血症模型中,两种 MBA 均被证明对耐甲氧西林金黄色葡萄球菌有效。我们的研究结果表明,MBAs 是一种结构多样且尚未被充分开发的抗菌脂二肽类化合物。利用合成生物信息学天然产物的方法对未充分探索的细菌类群进行研究,是发现新型生物医学相关制剂以应对抗菌药耐药性危机的一种有吸引力的策略。
Discovery of a family of menaquinone-targeting cyclic lipodepsipeptides for multidrug-resistant Gram-positive pathogens.
Menaquinone (MK) in bacterial membrane is an attractive target for the development of novel therapeutic agents. Mining the untapped chemical diversity encoded by Gram-negative bacteria presents an opportunity to identify additional MK-binding antibiotics (MBAs). By MK-binding motif searching of bioinformatically predicted linear non-ribosomal peptides from 14,298 sequenced genomes of 45 underexplored Gram-negative bacterial genera, here we identify a novel MBA structural family, including silvmeb and pseudomeb, using structure prediction-guided chemical synthesis. Both MBAs show rapid bacteriolysis by MK-dependent membrane depolarization to achieve their potent activities against a panel of Gram-positive pathogens. Furthermore, both MBAs are proven to be effective against methicillin-resistant Staphylococcus aureus in a murine peritonitis-sepsis model. Our findings suggest that MBAs are a kind of structurally diverse and still underexplored antibacterial lipodepsipeptide class. The interrogation of underexplored bacterial taxa using synthetic bioinformatic natural product methods is an appealing strategy for discovering novel biomedically relevant agents to confront the crisis of antimicrobial resistance.
期刊介绍:
Communications Biology is an open access journal from Nature Research publishing high-quality research, reviews and commentary in all areas of the biological sciences. Research papers published by the journal represent significant advances bringing new biological insight to a specialized area of research.