AUTHOR=Paudel Atmika , Hamamoto Hiroshi , Panthee Suresh , Kaneko Keiichi , Matsunaga Shigeki , Kanai Motomu , Suzuki Yutaka , Sekimizu Kazuhisa 

TITLE=A Novel Spiro-Heterocyclic Compound Identified by the Silkworm Infection Model Inhibits Transcription in Staphylococcus aureus

JOURNAL=Frontiers in Microbiology

VOLUME=8

YEAR=2017

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2017.00712

DOI=10.3389/fmicb.2017.00712

ISSN=1664-302X

ABSTRACT=<p>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 <italic>in vitro</italic> antimicrobial activity against methicillin-resistant <italic>Staphylococcus aureus</italic> and evaluated the <italic>in vivo</italic> therapeutic effectiveness of the hits in <italic>S. aureus</italic>-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 <italic>S. aureus</italic> cells. GPI0363-resistant <italic>S. aureus</italic> 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 <italic>in vitro</italic>, and prolong the survival of mice infected with methicillin-resistant <italic>S. aureus</italic>. Thus, GPI0363 is an attractive candidate therapeutic agent against drug-resistant <italic>S. aureus</italic> infections.</p>