Attenuating Staphylococcus aureus Virulence by Targeting Flotillin Protein Scaffold Activity. Issue 7 (20th July 2017)

• Record Type: Journal Article
• Authors: Koch, Gudrun; Wermser, Charlotte; Acosta, Ivan C.; Kricks, Lara; Stengel, Stephanie T.; Yepes, Ana; Lopez, Daniel
• Is Part Of: Cell chemical biology. Volume 24:Issue 7(2017)
• Page Start: 845
• Page End: 857.e6
• Publication Date: 2017-07-20
• Subjects: flotillin -- Staphylococcus -- Rny -- membrane organization; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2017.05.027
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: Scaffold proteins are ubiquitous chaperones that bind proteins and facilitate physical interaction of multi-enzyme complexes. Here we used a biochemical approach to dissect the scaffold activity of the flotillin-homolog protein FloA of the multi-drug-resistant human pathogen Staphylococcus aureus . We show that FloA promotes oligomerization of membrane protein complexes, such as the membrane-associated RNase Rny, which forms part of the RNA-degradation machinery called the degradosome. Cells lacking FloA had reduced Rny function and a consequent increase in the targeted sRNA transcripts that negatively regulate S. aureus toxin expression. Small molecules that altered FloA oligomerization also reduced Rny function and decreased the virulence potential of S. aureus in vitro, as well as in vivo, using invertebrate and murine infection models. Our results suggest that flotillin assists in the assembly of protein complexes involved in S. aureus virulence, and could thus be an attractive target for the development of new antimicrobial therapies. Graphical Abstract: Highlights: The membrane scaffold protein flotillin promotes protein oligomerization in S. aureus Flotillin scaffolds degradosome oligomerization to upregulate virulence in S. aureus Flotillin mutants show attenuated virulence in vitro and in vivo in infection models Flotillin-inhibiting compounds limit infections by multi-drug-resistant S. aureus Abstract : Scaffold proteins are ubiquitous proteins that facilitate physical interaction of multi-enzyme complexes. Thus, targeting scaffold proteins of pathogenic bacteria may prevent the development of infections by simultaneously inhibiting diverse multi-enzyme complexes that play a role in virulence. Here we present an example on the scaffold protein flotillin of the multi-drug-resistant pathogen Staphylococcus aureus and show how flotillin assists in the assembly of the degradosome, a protein complex that upregulates the expression of virulence genes in S. aureus . We identify several small-molecule compounds that alter flotillin oligomerization, thus affecting the degradosome activity and reducing S. aureus virulence during in vivo S. aureus infections that are resistant to conventional antibiotics. Flotillin could thus be an attractive target for the development of new antimicrobial therapies against multi-drug-resistant bacteria.