State Key Laboratory of Microbial Metabolism and School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 800 Dongchuan Rd., Shanghai, 200240, China.
State Key Laboratory of Bioreactor Engineering and School of Biotechnology, East China University of Science and Technology, 130 Meilong Rd., Shanghai, 200237, China.
Commun Biol. 2024 Nov 7;7(1):1453. doi: 10.1038/s42003-024-07159-5.
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.
细菌膜中的甲萘醌（MK）是开发新型治疗药物的有吸引力的靶标。挖掘革兰氏阴性细菌编码的未开发的化学多样性为识别其他 MK 结合抗生素（MBAs）提供了机会。通过对来自 45 个未充分研究的革兰氏阴性细菌属的 14298 个测序基因组中生物信息学预测的线性非核糖体肽进行基于 MK 结合基序的搜索，我们使用结构预测指导的化学合成，鉴定了一种新型 MBA 结构家族，包括 silvmeb 和 pseudomeb。这两种 MBA 都通过 MK 依赖性膜去极化导致快速细菌溶解，从而对一系列革兰氏阳性病原体表现出强大的活性。此外，这两种 MBA 在耐甲氧西林金黄色葡萄球菌的小鼠腹膜炎-败血症模型中均被证明有效。我们的研究结果表明，MBAs 是一种结构多样且仍未充分研究的抗菌脂肽类药物。使用合成生物信息学天然产物方法对未充分研究的细菌类群进行研究是发现新型具有生物医学相关性的药物以应对抗生素耐药性危机的一种有吸引力的策略。
