Programa de Pós-graduação Em Biotecnologia, Universidade Estadual de Feira de Santana, Brazil.
Centro de Ciências da Saúde da Universidade Federal de Santa Maria, Brazil.
Microb Pathog. 2020 Jul;144:104127. doi: 10.1016/j.micpath.2020.104127. Epub 2020 Mar 10.
Despite the main strategy to overcome bacterial resistance has focused on the development of more potent antimicrobial agents, the evolutionary pressure caused by such drugs makes this strategy limited. Molecules that interfere with virulence factors appear as a promising alternative though, as they cause reduced selective pressure. As a matter of fact, staphyloxanthin biosynthesis inhibition (STXBI) has been pursued as promising strategy to reduce S. aureus virulence. Herein, we report the inhibitory profile of 27 tetrangomycin derivatives over staphyloxanthin production. The experimental result showed that naphthoquinone dehydro-α-lapachone (25 - EC = 57.29 ± 1.15 μM) and 2-Isopropylnaphtho[2,3-b]furan-4,9-dione (26 EC = 82.10 ± 1.09 μM) are the most potent compounds and suggest that hydrogen acceptor groups and lipophilic moieties decorating the naphthoquinone ring are crucial for STXBI. In addition, we present an in situ analysis, through RAMAN spectroscopy, that is inexpensive and might be employed to probe the mechanism of action of staphyloxanthin biosynthesis inhibitors. Therefore, our molecular simplification strategies afforded promising lead compounds for the development of drugs that modulate S. aureus staphyloxanthin biosynthesis.
尽管克服细菌耐药性的主要策略集中在开发更有效的抗菌药物上，但这些药物所带来的进化压力使得这一策略受到限制。然而，干扰毒力因子的分子似乎是一种很有前途的替代方法，因为它们会降低选择压力。事实上，抑制金黄色葡萄球菌素生物合成（STXBI）已被视为降低金黄色葡萄球菌毒力的有前途的策略。在此，我们报告了 27 种四放线菌素衍生物对金黄色葡萄球菌素产生的抑制作用。实验结果表明，萘醌脱氢-α-拉帕醌（25-EC=57.29±1.15μM）和 2-异丙基萘[2,3-b]呋喃-4,9-二酮（26-EC=82.10±1.09μM）是最有效的化合物，这表明萘醌环上的氢受体基团和疏脂部分对于 STXBI 至关重要。此外，我们通过拉曼光谱进行了现场分析，这是一种廉价的方法，可用于探测金黄色葡萄球菌素生物合成抑制剂的作用机制。因此，我们的分子简化策略为开发调节金黄色葡萄球菌素生物合成的药物提供了有前途的先导化合物。
