SK-03-92 Treatment Causes Release of a Lethal Factor Protein That Kills Staphylococcus aureus Cells

Abstract

Background: Staphylococcus aureus is a leading cause of skin and bloodstream infections in humans. Antibiotic resistant strains of S. aureus continue to be a problem in treating patients that are infected, so treatment options are needed. A drug discovery project identified SK-03-92 as a novel anti-staphylococcal drug, but the SK-03-92 mechanism of action is unknown. We hypothesized that a lethal factor was being released by the bacteria that killed siblings. Methods: In this study, filtration through molecular weight cut-off filters as well as boiling, trypsin treatment, and proteinase K treatment were used to ascertain what the lethal factor was released by SK-03-92 treated S. aureus cells. Results: Filtration through molecular weight cut-off filters demonstrated the lethal factor released by SK-03-92 treated S. aureus cells had a molecular cut-off between 10,000 Da and 30,000 Da that killed fresh S. aureus cells but was not released by untreated cells. Through proteinase K digestion, trypsin digestion, and boiling experiments, the lethal factor was shown to be a protein. Further experiments are needed to identify what proteins released following SK-03-92 treatment cause the death of S. aureus cells. Conclusions: The data show that SK-03-92 treatment causes S. aureus to release a lethal factor protein that kills S. aureus cells, suggesting a new mechanism of action for an antibacterial drug.