Journal article
Therapeutic Inhibition of Staphylococcus aureus ArlRS Two-Component Regulatory System Blocks Virulence
Antimicrobial agents and chemotherapy, Vol.66(7), pp.e0018722-e0018722
06/23/2022
DOI: 10.1128/aac.00187-22
PMCID: PMC9295591
PMID: 35736133
Abstract
Staphylococcus aureus is a common cause of severe infections, and its widespread antibiotic resistance necessitates search for alternative therapies, such as inhibition of virulence. As S. aureus produces multiple individual virulence factors, inhibition of an entire regulatory system might provide better effects than targeting each virulence factor separately.
ABSTRACT Staphylococcus aureus is a common cause of severe infections, and its widespread antibiotic resistance necessitates search for alternative therapies, such as inhibition of virulence. As S. aureus produces multiple individual virulence factors, inhibition of an entire regulatory system might provide better effects than targeting each virulence factor separately. Herein, we describe two novel inhibitors of S. aureus two-component regulatory system ArlRS: 3,4’-dimethoxyflavone and homopterocarpin. Unlike other putative ArlRS inhibitors previously identified, these two compounds were effective and specific. In vitro kinase assays indicated that 3,4’-dimethoxyflavone directly inhibits ArlS autophosphorylation, while homopterocarpin did not exhibit such effect, suggesting that two inhibitors work through distinct mechanisms. Application of the inhibitors to methicillin-resistant S. aureus (MRSA) in vitro blocked ArlRS signaling, inducing an abnormal gene expression pattern that was reflected in changes at the protein level, enhanced sensitivity to oxacillin, and led to the loss of numerous cellular virulence traits, including the ability to clump, adhere to host ligands, and evade innate immunity. The pleiotropic antivirulence effect of inhibiting a single regulatory system resulted in a marked therapeutic potential, demonstrated by the ability of inhibitors to decrease severity of MRSA infection in mice. Altogether, this study demonstrated the feasibility of ArlRS inhibition as anti- S. aureus treatment, and identified new lead compounds for therapeutic development.
Details
- Title: Subtitle
- Therapeutic Inhibition of Staphylococcus aureus ArlRS Two-Component Regulatory System Blocks Virulence
- Creators
- Jakub M. Kwiecinski - University of Colorado DenverDiamond A. Jelani - University of IowaErnesto J. Fuentes - University of IowaAlexander R. Horswill - University of Colorado Denver
- Resource Type
- Journal article
- Publication Details
- Antimicrobial agents and chemotherapy, Vol.66(7), pp.e0018722-e0018722
- DOI
- 10.1128/aac.00187-22
- PMID
- 35736133
- PMCID
- PMC9295591
- ISSN
- 0066-4804
- eISSN
- 1098-6596
- Grant note
- DOI: 10.13039/100000738, name: U.S. Department of Veterans Affairs, award: BX002711; DOI: 10.13039/100000002, name: HHS | National Institutes of Health, award: AI141490; DOI: 10.13039/100000002, name: HHS | National Institutes of Health, award: AI153185
- Language
- English
- Date published
- 06/23/2022
- Academic Unit
- Biochemistry and Molecular Biology
- Record Identifier
- 9984288725802771
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