Department of Chemistry, National Taiwan University, 10617, Taipei City, Taiwan.
Helmholtz Institute for Pharmaceutical Research Saarland Helmholtz Centre for Infection Research, Saarland University Campus, 66123, Saarbrücken, Germany.
ChemMedChem. 2022 May 18;17(10):e202200075. doi: 10.1002/cmdc.202200075. Epub 2022 Mar 15.
The use of synergistic antibiotic combinations has emerged as a viable approach to contain the rapid spread of antibiotic-resistant pathogens. Here we report the discovery of a new strongly synergistic pair - microcin J25 and sulfamonomethoxine. The former is a lasso peptide that inhibits the function of RNA polymerase and the latter is a sulfonamide antibacterial agent that disrupts the folate pathway. Key to our discovery was a screening strategy that focuses on an antibiotic (microcin J25) that targets a hub (transcription) in the densely interconnected network of cellular pathways. The rationale was that disrupting such a hub likely weakens the entire network, generating weak links that potentiate the growth inhibitory effect of other antibiotics. We found that MccJ25 potentiates five other antibiotics as well. These results showcase the merit of taking a more targeted approach in the search and study of synergistic antibiotic pairs.
联合使用协同抗生素组合已成为遏制抗生素耐药性病原体快速传播的可行方法。在这里，我们报告了一种新的强协同对 - 微菌素 J25 和磺胺甲恶唑。前者是一种套索肽，可抑制 RNA 聚合酶的功能，后者是一种磺胺类抗菌药物，可破坏叶酸途径。我们发现的关键是一种筛选策略，该策略侧重于一种抗生素（微菌素 J25），该抗生素针对细胞途径的密集互联网络中的一个枢纽（转录）。其基本原理是，破坏这样的枢纽很可能会削弱整个网络，产生薄弱环节，从而增强其他抗生素的抑制生长作用。我们发现 MccJ25 还可以增强其他五种抗生素的作用。这些结果展示了在寻找和研究协同抗生素对时采取更有针对性方法的优点。
