Abstract
The mechanism of action for a new lead stilbene compound coded SK-03-92 with bactericidal activity against methicillin-resistant Staphylococcus aureus (MRSA) is unknown. To gain insight into the killing process, transcriptional profiling was performed on SK-03-92 treated vs. untreated S. aureus. Fourteen genes were upregulated and 38 genes downregulated by SK-03-92 treatment. Genes involved in sortase A production, protein metabolism, and transcriptional regulation were upregulated, whereas genes encoding transporters, purine synthesis proteins, and a putative two-component system (SACOL2360 (MW2284) and SACOL2361 (MW2285)) were downregulated by SK-03-92 treatment. Quantitative real-time polymerase chain reaction analyses validated upregulation of srtA and tdk as well as downregulation of the MW2284/MW2285 and purine biosynthesis genes in the drug-treated population. A quantitative real-time polymerase chain reaction analysis of MW2284 and MW2285 mutants compared to wild-type cells demonstrated that the srtA gene was upregulated by both putative two-component regulatory gene mutants compared to the wild-type strain. Using a transcription profiling technique, we have identified several cellular pathways regulated by SK-03-92 treatment, including a putative two-component system that may regulate srtA and other genes that could be tied to the SK-03-92 mechanism of action, biofilm formation, and drug persisters.
Highlights
Staphylococcus aureus is a common inhabitant of the human body that causes numerous infections, including skin and soft tissue infections as well as more serious infections, such as pneumonia and bacteremia [1]
To ascertain the effects of SK-03-92 treatment on the transcriptome of S. aureus, total RNA was isolated from S. aureus strain MW2 cultures (Table 1) treated for 30 min with 8× the minimum inhibitory concentration (MIC) of SK-03-92 and untreated MW2 cultures and an RNA microarray was performed
Consistent with the formation of persister strains, mRNA levels of genes linked to programmed cell death (PCD) were decreased in S. aureus cultures treated with SK-03-92
Summary
Staphylococcus aureus is a common inhabitant of the human body that causes numerous infections, including skin and soft tissue infections as well as more serious infections, such as pneumonia and bacteremia [1]. Around 60% of S. aureus clinical isolates are methicillin-resistant S. aureus (MRSA) [2], and this bacterium is a leading cause of nosocomial infections in the United States [3,4]. Strains emerged in the United States, causing infections in younger people, including necrotizing pneumonia [5,6,7]. New drugs are needed to treat MRSA infections; most drugs currently in development are derivatives of drugs already being marketed [18,19]. S. aureus is one of the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter species) targeted by the 10 × 20 initiative to develop 10 new, safe and effective antibiotics approved by 2020 [20]. Many drugs used to treat S. aureus infections have drug persister population emerge that are recalcitrant to treatment. To gain insight into the mechanism of action of SK-03-92 and the mechanism of S. aureus persistence to SK-03-92 treatment, the effect of SK-03-92 on S. aureus cells was assessed by transcriptional profiling in the S. aureus strain MW2
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