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Cell Rep. 2019 Apr 2;27(1):187-198.e6. doi: 10.1016/j.celrep.2019.03.018.

Apicidin Attenuates MRSA Virulence through Quorum-Sensing Inhibition and Enhanced Host Defense.

Author information

1
Roy J. and Lucille A. Carver College of Medicine, Department of Microbiology, University of Iowa, Iowa City, IA, USA.
2
Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, USA.
3
Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, NC, USA.
4
Mycosynthetix, Inc., Hillsborough, NC, USA.
5
Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, USA; Department of Veterans Affairs, Eastern Colorado Healthcare System, Aurora, CO, USA. Electronic address: alexander.horswill@ucdenver.edu.

Abstract

Recurrent epidemics of drug-resistant Staphylococcus aureus illustrate the rapid lapse of antibiotic efficacy following clinical implementation. Over the last decade, community-associated methicillin-resistant S. aureus (MRSA) has emerged as a dominant cause of infections, and this problem is amplified by the hyper-virulent nature of these isolates. Herein, we report the discovery of a fungal metabolite, apicidin, as an innovative means to counter both resistance and virulence. Owing to its breadth and specificity as a quorum-sensing inhibitor, apicidin antagonizes all MRSA agr systems in a non-biocidal manner. In skin challenge experiments, the apicidin-mediated abatement of MRSA pathogenesis corresponds with quorum-sensing inhibition at in vivo sites of infection. Additionally, we show that apicidin attenuates MRSA-induced disease by potentiating innate effector responses, particularly through enhanced neutrophil accumulation and function at cutaneous challenge sites. Together, these results indicate that apicidin treatment represents a strategy to limit MRSA virulence and promote host defense.

KEYWORDS:

MRSA; Staphylococcus aureus; agr; apicidin; natural product; pathogenesis; quorum sensing; skin infection

PMID:
30943400
DOI:
10.1016/j.celrep.2019.03.018
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