Small-molecule AgrA inhibitors F12 and F19 act as antivirulence agents against Gram-positive pathogens View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2018-10-01

AUTHORS

Michael Greenberg, David Kuo, Eckhard Jankowsky, Lisa Long, Chris Hager, Kiran Bandi, Danyang Ma, Divya Manoharan, Yaron Shoham, William Harte, Mahmoud A. Ghannoum, Menachem Shoham

ABSTRACT

Small-molecule antivirulence agents represent a promising alternative or adjuvant to antibiotics. These compounds disarm pathogens of disease-causing toxins without killing them, thereby diminishing survival pressure to develop resistance. Here we show that the small-molecule antivirulence agents F12 and F19 block staphylococcal transcription factor AgrA from binding to its promoter. Consequently, toxin expression is inhibited, thus preventing host cell damage by Gram-positive pathogens. Broad spectrum efficacy against Gram-positive pathogens is due to the existence of AgrA homologs in many Gram-positive bacteria. F12 is more efficacious in vitro and F19 works better in vivo. In a murine MRSA bacteremia/sepsis model, F19 treatment alone resulted in 100% survival while untreated animals had 70% mortality. Furthermore, F19 enhances antibiotic efficacy in vivo. Notably, in a murine MRSA wound infection model, combination of F19 with antibiotics resulted in bacterial load reduction. Thus, F19 could be used alone or in combination with antibiotics to prevent and treat infections of Gram-positive pathogens. More... »

PAGES

14578

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41598-018-32829-w

DOI

http://dx.doi.org/10.1038/s41598-018-32829-w

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1107245492

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/30275455


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