Identification of small molecules exhibiting oxacillin synergy through a novel assay for inhibition of vraTSR expression in methicillin-resistant staphylococcus aureus

Hyun Lee, Susan Boyle-Vavra, Jinhong Ren, Jamie A. Jarusiewicz, Lalit Kumar Sharma, Daniel T. Hoagland, Shaohui Yin, Tian Zhu, Kirk Hevener, Isabel Ojeda, Richard E. Lee, Robert S. Daum, Michael E. Johnson

Research output: Contribution to journalArticle

Abstract

Methicillin-resistant Staphylococcus aureus (MRSA) strains that are resistant to all forms of penicillin have become an increasingly common and urgent problem threatening human health. They are responsible for a wide variety of infectious diseases ranging from minor skin abscesses to life-threatening severe infections. The vra operon that is conserved among S. aureus strains encodes a three-component signal transduction system (vraTSR) that is responsible for sensing and responding to cell wall stress. We developed a novel and multifaceted assay to identify compounds that potentiate the activity of oxacillin, essentially restoring efficacy of oxacillin against MRSA, and performed high-throughput screening (HTS) to identify oxacillin potentiators. HTS of 13,840 small-molecule compounds from an antimicrobial-focused Life Chemicals library, using the MRSA cell-based assay, identified three different inhibitor scaffolds. Checkerboard assays for synergy with oxacillin, reverse transcriptase PCR (RT-PCR) assays against vraR expression, and direct confirmation of interaction with VraS by surface plasmon resonance (SPR) further verified them to be viable hit compounds. A subsequent structure-activity relationship (SAR) study of the best scaffold with diverse analogs was utilized to improve potency and provides a strong foundation for further development.

Original languageEnglish (US)
Article numbere02593-18
JournalAntimicrobial Agents and Chemotherapy
Volume63
Issue number9
DOIs
StatePublished - Jan 1 2019

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Oxacillin
Methicillin-Resistant Staphylococcus aureus
Small Molecule Libraries
Surface Plasmon Resonance
Structure-Activity Relationship
Operon
Microbiology
Reverse Transcriptase Polymerase Chain Reaction
Penicillins
Abscess
Cell Wall
Communicable Diseases
Staphylococcus aureus
Signal Transduction
Skin
Histidine Kinase
Health
Infection

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

Identification of small molecules exhibiting oxacillin synergy through a novel assay for inhibition of vraTSR expression in methicillin-resistant staphylococcus aureus. / Lee, Hyun; Boyle-Vavra, Susan; Ren, Jinhong; Jarusiewicz, Jamie A.; Sharma, Lalit Kumar; Hoagland, Daniel T.; Yin, Shaohui; Zhu, Tian; Hevener, Kirk; Ojeda, Isabel; Lee, Richard E.; Daum, Robert S.; Johnson, Michael E.

In: Antimicrobial Agents and Chemotherapy, Vol. 63, No. 9, e02593-18, 01.01.2019.

Research output: Contribution to journalArticle

Lee, H, Boyle-Vavra, S, Ren, J, Jarusiewicz, JA, Sharma, LK, Hoagland, DT, Yin, S, Zhu, T, Hevener, K, Ojeda, I, Lee, RE, Daum, RS & Johnson, ME 2019, 'Identification of small molecules exhibiting oxacillin synergy through a novel assay for inhibition of vraTSR expression in methicillin-resistant staphylococcus aureus', Antimicrobial Agents and Chemotherapy, vol. 63, no. 9, e02593-18. https://doi.org/10.1128/AAC.02593-18
Lee, Hyun ; Boyle-Vavra, Susan ; Ren, Jinhong ; Jarusiewicz, Jamie A. ; Sharma, Lalit Kumar ; Hoagland, Daniel T. ; Yin, Shaohui ; Zhu, Tian ; Hevener, Kirk ; Ojeda, Isabel ; Lee, Richard E. ; Daum, Robert S. ; Johnson, Michael E. / Identification of small molecules exhibiting oxacillin synergy through a novel assay for inhibition of vraTSR expression in methicillin-resistant staphylococcus aureus. In: Antimicrobial Agents and Chemotherapy. 2019 ; Vol. 63, No. 9.
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