Paudel Atmika, Hamamoto Hiroshi, Panthee Suresh, Kaneko Keiichi, Matsunaga Shigeki, Kanai Motomu, Suzuki Yutaka, Sekimizu Kazuhisa
Institute of Medical Mycology, Teikyo UniversityHachioji, Tokyo, Japan.
Laboratory of Synthetic Organic Chemistry, Graduate School of Pharmaceutical Sciences, The University of TokyoTokyo, Japan.
Front Microbiol. 2017 Apr 25;8:712. doi: 10.3389/fmicb.2017.00712. eCollection 2017.
Synthetic compounds are a vital source of antimicrobial agents. To uncover therapeutically effective antimicrobial agents from a chemical library, we screened over 100,000 synthetic compounds for antimicrobial activity against methicillin-resistant and evaluated the therapeutic effectiveness of the hits in -infected silkworms. Three antimicrobial agents exhibited therapeutic effects in the silkworm infection model. One of these, GPI0363, a novel spiro-heterocyclic compound, was bacteriostatic and inhibited RNA synthesis in cells. GPI0363-resistant strains harbored a point mutation in the gene encoding the primary sigma factor, SigA, of RNA polymerase, and this mutation was responsible for the resistance to GPI0363. We further revealed that GPI0363 could bind to SigA, inhibit promoter-specific transcription , and prolong the survival of mice infected with methicillin-resistant . Thus, GPI0363 is an attractive candidate therapeutic agent against drug-resistant infections.
合成化合物是抗菌剂的重要来源。为了从化学文库中发现具有治疗效果的抗菌剂，我们筛选了超过10万种合成化合物，检测其对耐甲氧西林菌的抗菌活性，并评估了筛选出的化合物在感染家蚕中的治疗效果。三种抗菌剂在蚕感染模型中显示出治疗效果。其中一种名为GPI0363的新型螺杂环化合物具有抑菌作用，并能抑制细胞中的RNA合成。对GPI0363耐药的菌株在编码RNA聚合酶主要σ因子SigA的基因中存在一个点突变，该突变导致了对GPI0363的耐药性。我们进一步发现，GPI0363可以与SigA结合，抑制启动子特异性转录，并延长耐甲氧西林感染小鼠的存活时间。因此，GPI0363是一种有吸引力的抗耐药菌感染治疗候选药物。
