A Novel Spiro-Heterocyclic Compound Identified by the Silkworm Infection Model Inhibits Transcription in .

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.