Identifying the lethal factor protein secreted by Staphylococcus aureus treatment with SK-03-92 drug

Abstract

Drug resistant strains of Staphylococcus aureus are an ongoing problem in treating human infections. To address this problem, a compound called SK-03-92 was previously synthesized and demonstrated antimicrobial properties with an unknown mechanism of action. A prior RNA microarray of SK-03-92 treated S. aureus cells showed transcriptional dysregulation of the lrgA, srtA, brpR, and brpS genes versus untreated cells. Homology of the S. aureus BrpRS system to the ComDE two-component system in S. mutans suggested SK-03-92 treatment may induce the secretion of a lethal factor protein from S. aureus cells. In this study, bioinformatic analysis suggests the brpRS genes encode for proteins that make up a LytTR regulatory system. Moreover, SK-03-92 treated S. aureus supernatants that were boiled or digested with proteinase K lost their killing activity, verifying the lethal factor was a protein. Through one-dimensional gel electrophoresis, an approximate 13 kDa protein was observed in SK-03-92 treated supernatant that was absent in the untreated supernatant. Further proteomic analysis revealed several proteins in SK-03-92 treated samples that significantly varied in concentration compared to untreated samples, and these proteins may be tied to quorum sensing within S. aureus. Further research is required to understand the mechanism of action of SK-03-92.