Paudel Atmika, Panthee Suresh, Hamamoto Hiroshi, Sekimizu Kazuhisa
Teikyo University Institute of Medical Mycology 359 Otsuka, Hachioji Tokyo 192-0395 Japan
Genome Pharmaceuticals Institute 102 Next Building, 3-24-17 Hongo, Bunkyo-ku Tokyo 113-0033 Japan.
RSC Adv. 2019 Nov 21;9(65):37889-37894. doi: 10.1039/c9ra06844a. eCollection 2019 Nov 19.
We previously reported a therapeutically effective spiro-heterocyclic compound, GPI0363, that inhibits the transcription of the primary sigma factor of RNA polymerase, SigA. Here, we demonstrated that GPI0363 shares no cross-resistance with the clinically used RNA polymerase inhibitors rifampicin and fidaxomicin. Furthermore, we found that GPI0363 bound to SigA of both GPI0363-susceptible and resistant strains, and inhibited the interaction of the RNA polymerase holoenzyme with DNA. In addition, the gene expression patterns following GPI0363 treatment were different from those following rifampicin treatment. These findings suggest that GPI0363 has a unique mechanism of action and can serve as a promising lead molecule to develop staphylococcal RNA polymerase inhibitors.
我们之前报道了一种具有治疗效果的螺环杂环化合物GPI0363，它能抑制RNA聚合酶的主要σ因子SigA的转录。在此，我们证明GPI0363与临床使用的RNA聚合酶抑制剂利福平和非达霉素不存在交叉耐药性。此外，我们发现GPI0363与GPI0363敏感和耐药菌株的SigA均结合，并抑制RNA聚合酶全酶与DNA的相互作用。另外，GPI0363处理后的基因表达模式与利福平处理后的不同。这些发现表明GPI0363具有独特的作用机制，可作为开发葡萄球菌RNA聚合酶抑制剂的有前景的先导分子。
