. 2017 Sep 11;6(3):17.

doi: 10.3390/antibiotics6030017.

Identification of Staphylococcus aureus Cellular Pathways Affected by the Stilbenoid Lead Drug SK-03-92 Using a Microarray

William R Schwan^{1

2}, Rebecca Polanowski^{3

4}, Paul M Dunman⁵, Sara Medina-Bielski^{6

7}, Michelle Lane^{8

9}, Marc Rott^{10

11}, Lauren Lipker^{12

13}, Amy Wescott^{14

15}, Aaron Monte^{16

17}, James M Cook¹⁸, Douglas D Baumann¹⁹, V V N Phani Babu Tiruveedhula²⁰, Christopher M Witzigmann²¹, Cassandra Mikel^{22

23}, Md Toufiqur Rahman²⁴

Affiliations

¹ Department of Microbiology, University of Wisconsin-La Crosse, La Crosse, WI 54601, USA. wschwan@uwlax.edu.
² Emerging Technology Center for Pharmaceutical Development, University of Wisconsin-La Crosse, La Crosse, WI 54601, USA. wschwan@uwlax.edu.
³ Department of Microbiology, University of Wisconsin-La Crosse, La Crosse, WI 54601, USA. rpolanowski@uwlax.edu.
⁴ Emerging Technology Center for Pharmaceutical Development, University of Wisconsin-La Crosse, La Crosse, WI 54601, USA. rpolanowski@uwlax.edu.
⁵ School of Medicine and Dentistry, University of Rochester, Rochester, NY 14642, USA. paul_dunman@urmc.rochester.edu.
⁶ Department of Microbiology, University of Wisconsin-La Crosse, La Crosse, WI 54601, USA. s.medinabielski@gmail.com.
⁷ Emerging Technology Center for Pharmaceutical Development, University of Wisconsin-La Crosse, La Crosse, WI 54601, USA. s.medinabielski@gmail.com.
⁸ Department of Microbiology, University of Wisconsin-La Crosse, La Crosse, WI 54601, USA. lanem7285@gmail.com.
⁹ Emerging Technology Center for Pharmaceutical Development, University of Wisconsin-La Crosse, La Crosse, WI 54601, USA. lanem7285@gmail.com.
¹⁰ Department of Microbiology, University of Wisconsin-La Crosse, La Crosse, WI 54601, USA. mrott@uwlax.edu.
¹¹ Emerging Technology Center for Pharmaceutical Development, University of Wisconsin-La Crosse, La Crosse, WI 54601, USA. mrott@uwlax.edu.
¹² Department of Microbiology, University of Wisconsin-La Crosse, La Crosse, WI 54601, USA. lipker.laur@uwlax.edu.
¹³ Emerging Technology Center for Pharmaceutical Development, University of Wisconsin-La Crosse, La Crosse, WI 54601, USA. lipker.laur@uwlax.edu.
¹⁴ Department of Microbiology, University of Wisconsin-La Crosse, La Crosse, WI 54601, USA. amywescott16@gmail.com.
¹⁵ Emerging Technology Center for Pharmaceutical Development, University of Wisconsin-La Crosse, La Crosse, WI 54601, USA. amywescott16@gmail.com.
¹⁶ Emerging Technology Center for Pharmaceutical Development, University of Wisconsin-La Crosse, La Crosse, WI 54601, USA. amonte@uwlax.edu.
¹⁷ Department of Chemistry and Biochemistry, University of Wisconsin-La Crosse, La Crosse, WI 54601, USA. amonte@uwlax.edu.
¹⁸ Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI 53211, USA. capncook@uwm.edu.
¹⁹ Department of Mathematics and Statistics, University of Wisconsin-La Crosse, La Crosse, WI 54601, USA. dbaumann@uwlax.edu.
²⁰ Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI 53211, USA. tiruvee2@uwm.edu.
²¹ Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI 53211, USA. witzigm2@uwm.edu.
²² Department of Microbiology, University of Wisconsin-La Crosse, La Crosse, WI 54601, USA. cassandra.mm010@gmail.com.
²³ Emerging Technology Center for Pharmaceutical Development, University of Wisconsin-La Crosse, La Crosse, WI 54601, USA. cassandra.mm010@gmail.com.
²⁴ Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI 53211, USA. mdrahman@uwm.edu.

PMID: 28892020
PMCID: PMC5617981
DOI: 10.3390/antibiotics6030017

Identification of Staphylococcus aureus Cellular Pathways Affected by the Stilbenoid Lead Drug SK-03-92 Using a Microarray

William R Schwan et al. Antibiotics (Basel). 2017.

. 2017 Sep 11;6(3):17.

doi: 10.3390/antibiotics6030017.

Authors

Affiliations

¹ Department of Microbiology, University of Wisconsin-La Crosse, La Crosse, WI 54601, USA. wschwan@uwlax.edu.
² Emerging Technology Center for Pharmaceutical Development, University of Wisconsin-La Crosse, La Crosse, WI 54601, USA. wschwan@uwlax.edu.
³ Department of Microbiology, University of Wisconsin-La Crosse, La Crosse, WI 54601, USA. rpolanowski@uwlax.edu.
⁴ Emerging Technology Center for Pharmaceutical Development, University of Wisconsin-La Crosse, La Crosse, WI 54601, USA. rpolanowski@uwlax.edu.
⁵ School of Medicine and Dentistry, University of Rochester, Rochester, NY 14642, USA. paul_dunman@urmc.rochester.edu.
⁶ Department of Microbiology, University of Wisconsin-La Crosse, La Crosse, WI 54601, USA. s.medinabielski@gmail.com.
⁷ Emerging Technology Center for Pharmaceutical Development, University of Wisconsin-La Crosse, La Crosse, WI 54601, USA. s.medinabielski@gmail.com.
⁸ Department of Microbiology, University of Wisconsin-La Crosse, La Crosse, WI 54601, USA. lanem7285@gmail.com.
⁹ Emerging Technology Center for Pharmaceutical Development, University of Wisconsin-La Crosse, La Crosse, WI 54601, USA. lanem7285@gmail.com.
¹⁰ Department of Microbiology, University of Wisconsin-La Crosse, La Crosse, WI 54601, USA. mrott@uwlax.edu.
¹¹ Emerging Technology Center for Pharmaceutical Development, University of Wisconsin-La Crosse, La Crosse, WI 54601, USA. mrott@uwlax.edu.
¹² Department of Microbiology, University of Wisconsin-La Crosse, La Crosse, WI 54601, USA. lipker.laur@uwlax.edu.
¹³ Emerging Technology Center for Pharmaceutical Development, University of Wisconsin-La Crosse, La Crosse, WI 54601, USA. lipker.laur@uwlax.edu.
¹⁴ Department of Microbiology, University of Wisconsin-La Crosse, La Crosse, WI 54601, USA. amywescott16@gmail.com.
¹⁵ Emerging Technology Center for Pharmaceutical Development, University of Wisconsin-La Crosse, La Crosse, WI 54601, USA. amywescott16@gmail.com.
¹⁶ Emerging Technology Center for Pharmaceutical Development, University of Wisconsin-La Crosse, La Crosse, WI 54601, USA. amonte@uwlax.edu.
¹⁷ Department of Chemistry and Biochemistry, University of Wisconsin-La Crosse, La Crosse, WI 54601, USA. amonte@uwlax.edu.
¹⁸ Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI 53211, USA. capncook@uwm.edu.
¹⁹ Department of Mathematics and Statistics, University of Wisconsin-La Crosse, La Crosse, WI 54601, USA. dbaumann@uwlax.edu.
²⁰ Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI 53211, USA. tiruvee2@uwm.edu.
²¹ Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI 53211, USA. witzigm2@uwm.edu.
²² Department of Microbiology, University of Wisconsin-La Crosse, La Crosse, WI 54601, USA. cassandra.mm010@gmail.com.
²³ Emerging Technology Center for Pharmaceutical Development, University of Wisconsin-La Crosse, La Crosse, WI 54601, USA. cassandra.mm010@gmail.com.
²⁴ Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI 53211, USA. mdrahman@uwm.edu.

PMID: 28892020
PMCID: PMC5617981
DOI: 10.3390/antibiotics6030017

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.

Keywords: Staphylococcus aureus; biofilm; drug mechanism of action; gene regulation; microarray; sortase; stilbene.

PubMed Disclaimer

Conflict of interest statement

W.R.S., M.R., A.M., and J.M.C. hold a composition of matter and use a patent covering the SK-03-92 lead compound.

Figures

**Figure 1**
Quantitative reverse transcribed-polymerase chain reaction results of *S. aureus* MW2 cells treated with 8× the SK-03-92 MIC vs. untreated cells. The data represents the mean + standard deviation from at least three separate runs.

**Figure 2**
Absorbance (254 and 280 nm) of the formic acid extracted nucleotide pool of log-phase *S. aureus* ATCC 29213 after 20 min with either (A) no treatment, (B) 60 μg/mL mupirocin, or (C) 16 μg/mL SK-03-92. Arrow denotes the (p)ppGpp peak.

**Figure 3**
The effects of SK-03-92 drug concentration on 24 h biofilm formation (OD₅₇₀) for *S. aureus* strains JE2 (black column) and MW2 (white column). All experiments represent the mean + standard deviation of at least 10 runs done in triplicate.

**Figure 4**
Quantitative reverse transcribed-polymerase chain reaction results of *S. aureus srtA* transcription in wild-type bacteria compared to MW2284 and MW2285 mutants. The data represents the mean + standard deviation from three separate runs.

See this image and copyright information in PMC

Cited by

Regulation of the Staphylococcal Superantigen-Like Protein 1 Gene of Community-Associated Methicillin-Resistant Staphylococcus aureus in Murine Abscesses.
Bretl DJ, Elfessi A, Watkins H, Schwan WR. Bretl DJ, et al. Toxins (Basel). 2019 Jul 4;11(7):391. doi: 10.3390/toxins11070391. Toxins (Basel). 2019. PMID: 31277443 Free PMC article.

References

1. Suaya J.A., Mera R.M., Cassidy A., O′Hara P., Amrine-Madsen H., Burstin S., Miller L.G. Incidence and cost of hospitalizations associated with Staphylococcus aureus skin and soft tissue infections in the United States from 2001 to 2009. BMC Infect. Dis. 2014;14:296. doi: 10.1186/1471-2334-14-296. - DOI - PMC - PubMed
1. Klein E.Y., Sun L., Smith D.L., Laxminarayan R. The changing epidemiology of methicillin-resistant Staphylococcus aureus in the United States: A national observational study. Am. J. Epidemiol. 2013;177:666–674. doi: 10.1093/aje/kws273. - DOI - PubMed
1. Hidron A.I., Edwards J.R., Patel J., Horan T.C., Sievert D.M., Pollock D.A., Fridkin S.K., National Healthcare Safety Network Team. Participating National Healthcare Safety Network Facilities NHSN annual update: Antimicrobial-resistant pathogens associated with healthcare-associated infections: Annual summary of data reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2006–2007. Infect. Control Hosp. Epidemiol. 2008;29:996–1011. - PubMed
1. Maree C.L., Daum R., Boyle-Vavra S., Matayoshi K., Miller L. Community associated methicillin-resistant Staphylococcus aureus isolates causing healthcare-associated infections. Emerg. Infect. Dis. 2007;13:236–242. doi: 10.3201/eid1302.060781. - DOI - PMC - PubMed
1. Herold B.C., Immergluck L.C., Maranan M.C., Lauderdale D.S., Gaskin R.E., Boyle-Vavra S., Leitch C.D., Daum R.S. Community-acquired methicillin-resistant Staphylococcus aureus in children with no identified predisposing risk. JAMA. 1998;279:593–598. doi: 10.1001/jama.279.8.593. - DOI - PubMed

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Identification of Staphylococcus aureus Cellular Pathways Affected by the Stilbenoid Lead Drug SK-03-92 Using a Microarray

Affiliations

Identification of Staphylococcus aureus Cellular Pathways Affected by the Stilbenoid Lead Drug SK-03-92 Using a Microarray

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