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

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