title: ω-Hydroxyemodin limits staphylococcus aureus quorum sensing-mediated pathogenesis and inflammation.
abstract: Antibiotic-resistant pathogens are a global health threat. Small molecules that inhibit bacterial virulence have been suggested as alternatives or adjuncts to conventional antibiotics, as they may limit pathogenesis and increase bacterial susceptibility to host killing. Staphylococcus aureus is a major cause of invasive skin and soft tissue infections (SSTIs) in both the hospital and community settings, and it is also becoming increasingly antibiotic resistant. Quorum sensing (QS) mediated by the accessory gene regulator (agr) controls virulence factor production essential for causing SSTIs. We recently identified ω-hydroxyemodin (OHM), a polyhydroxyanthraquinone isolated from solid-phase cultures of Penicillium restrictum, as a suppressor of QS and a compound sought for the further characterization of the mechanism of action. At concentrations that are nontoxic to eukaryotic cells and subinhibitory to bacterial growth, OHM prevented agr signaling by all four S. aureus agr alleles. OHM inhibited QS by direct binding to AgrA, the response regulator encoded by the agr operon, preventing the interaction of AgrA with the agr P2 promoter. Importantly, OHM was efficacious in a mouse model of S. aureus SSTI. Decreased dermonecrosis with OHM treatment was associated with enhanced bacterial clearance and reductions in inflammatory cytokine transcription and expression at the site of infection. Furthermore, OHM treatment enhanced the immune cell killing of S. aureus in vitro in an agr-dependent manner. These data suggest that bacterial disarmament through the suppression of S. aureus QS may bolster the host innate immune response and limit inflammation.
authors: Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, Albuquerque, New Mexico, USA.
authors: Seth M
authors: SM
authors: Daly
authors: Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, Albuquerque, New Mexico, USA.
authors: Bradley O
authors: BO
authors: Elmore
authors: Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.
authors: Jeffrey S
authors: JS
authors: Kavanaugh
authors: Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, Albuquerque, New Mexico, USA.
authors: Kathleen D
authors: KD
authors: Triplett
authors: Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina, USA.
authors: Mario
authors: M
authors: Figueroa
authors: Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina, USA.
authors: Huzefa A
authors: HA
authors: Raja
authors: Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina, USA.
authors: Tamam
authors: T
authors: El-Elimat
authors: Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.
authors: Heidi A
authors: HA
authors: Crosby
authors: Department of Emergency Medicine, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA.
authors: Jon K
authors: JK
authors: Femling
authors: Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina, USA.
authors: Nadja B
authors: NB
authors: Cech
authors: Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.
authors: Alexander R
authors: AR
authors: Horswill
authors: Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, North Carolina, USA.
authors: Nicholas H
authors: NH
authors: Oberlies
authors: Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, Albuquerque, New Mexico, USA phall@salud.unm.edu.
authors: Pamela R
authors: PR
authors: Hall
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics; D016207:Cytokines / Q000096:biosynthesis; D004642:Emodin / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007249:Inflammation / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D007962:Leukocytes / Q000382:microbiology; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D051379:Mice; D008958:Models, Molecular; D053038:Quorum Sensing / Q000187:drug effects*; D011817:Rabbits; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000382:microbiology* / Q000473:pathology; D015534:Trans-Activators / Q000235:genetics; D037521:Virulence Factors / Q000378:metabolism
chemical_list: C095698:Agr protein, Staphylococcus aureus; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D016207:Cytokines; D015534:Trans-Activators; D037521:Virulence Factors; C053854:1,3,8-trihydroxy-6-hydroxymethylanthraquinone; D004642:Emodin
references: N Engl J Med. 1998 Aug 20;339(8):520-32
references: 9709046
references: FEBS Lett. 1999 May 7;450(3):257-62
references: 10359085
references: J Antibiot (Tokyo). 1964 Jul;17:148-55
references: 14194952
references: Proc Natl Acad Sci U S A. 2005 Feb 1;102(5):1691-6
references: 15665088
references: J Immunol. 2005 Sep 15;175(6):3907-19
references: 16148137
references: Nat Rev Microbiol. 2005 Dec;3(12):948-58
references: 16322743
references: J Infect Dis. 2006 Mar 15;193(6):841-8
references: 16479519
references: N Engl J Med. 2006 Aug 17;355(7):666-74
references: 16914702
references: J Bacteriol. 2007 Jan;189(2):531-9
references: 17085555
references: Anal Bioanal Chem. 2007 Jan;387(2):437-44
references: 17072597
references: J Microbiol Methods. 2007 Jul;70(1):186-90
references: 17512993
references: Chem Biol. 2007 Oct;14(10):1119-27
references: 17961824
references: J Immunol. 2007 Nov 15;179(10):6933-42
references: 17982084
references: Nat Med. 2007 Dec;13(12):1510-4
references: 17994102
references: Biochemistry. 2007 Dec 18;46(50):14349-58
references: 18020451
references: Nat Rev Microbiol. 2008 Jan;6(1):17-27
references: 18079741
references: PLoS One. 2008;3(1):e1409
references: 18183290
references: J Exp Med. 2008 Feb 18;205(2):287-94
references: 18268041
references: PLoS One. 2010;5(12):e15177
references: 21151999
references: Chem Rev. 2011 Jan 12;111(1):117-51
references: 21174435
references: Planta Med. 2011 Jan;77(2):188-95
references: 20645243
references: BMC Microbiol. 2011;11:16
references: 21251258
references: Infect Immun. 2011 May;79(5):1927-35
references: 21402769
references: J Infect Dis. 2011 Sep 15;204(6):937-41
references: 21849291
references: Appl Microbiol Biotechnol. 2011 Oct;92(1):1-11
references: 21796380
references: Antimicrob Agents Chemother. 2012 Feb;56(2):787-804
references: 22106209
references: Semin Immunopathol. 2012 Mar;34(2):237-59
references: 22080185
references: Semin Immunopathol. 2012 Mar;34(2):299-315
references: 22089960
references: Semin Immunopathol. 2012 Mar;34(2):201-14
references: 22095240
references: Semin Immunopathol. 2012 Mar;34(2):185-200
references: 22160374
references: Cell Mol Life Sci. 2008 Mar;65(6):928-39
references: 18049859
references: Antimicrob Agents Chemother. 2012 Jun;56(6):3157-64
references: 22411615
references: Proc Natl Acad Sci U S A. 2012 Jun 5;109(23):9095-100
references: 22586129
references: J Microbiol Biotechnol. 2012 Aug;22(8):1170-6
references: 22713997
references: Sci Transl Med. 2012 Jun 27;4(140):140sr2
references: 22745440
references: Nat Methods. 2012 Jul;9(7):671-5
references: 22930834
references: Science. 2012 Aug 31;337(6098):1115-9
references: 22837383
references: Planta Med. 2012 Sep;78(14):1556-61
references: 22814821
references: Cold Spring Harb Perspect Med. 2012 Nov;2(11). pii: a012427. doi: 10.1101/cshperspect.a012427
references: 23125205
references: PLoS Pathog. 2012;8(11):e1003047
references: 23209417
references: Biochemistry. 2012 Dec 18;51(50):10035-43
references: 23181972
references: N Engl J Med. 2013 Jan 24;368(4):299-302
references: 23343059
references: MBio. 2013;4(1):e00537-12
references: 23404398
references: PLoS Pathog. 2013 Feb;9(2):e1003166
references: 23459693
references: Sensors (Basel). 2013;13(4):5130-66
references: 23598501
references: Immunol Lett. 2013 Feb;150(1-2):12-22
references: 23376548
references: Methods Mol Biol. 2013;1031:109-16
references: 23824894
references: Toxins (Basel). 2013 Jun;5(6):1140-66
references: 23888516
references: Curr Opin Pharmacol. 2013 Oct;13(5):688-98
references: 23876839
references: PLoS One. 2013;8(10):e75103
references: 24098366
references: Future Microbiol. 2013 Dec;8(12):1511-4
references: 24266350
references: Biochemistry. 2013 Dec 23;52(51):9358-66
references: 24251551
references: Methods Mol Biol. 2014;1124:13-8
references: 24504943
references: J Immunol. 2014 May 15;192(10):4709-17
references: 24729616
references: PLoS Pathog. 2014 Jun;10(6):e1004174
references: 24945495
references: J Nat Prod. 2014 Jun 27;77(6):1351-8
references: 24911880
references: Bioorg Chem. 2014 Aug;55:60-8
references: 24823895
references: J Bacteriol. 2014 Oct;196(19):3482-93
references: 25070736
references: J Infect Dis. 2014 Oct 1;210(7):1012-8
references: 24740631
references: Nucleic Acids Res. 2014 Nov 10;42(20):12523-36
references: 25352558
references: Clin Infect Dis. 2008 Jun 1;46 Suppl 5:S350-9
references: 18462090
references: Structure. 2008 May;16(5):727-35
references: 18462677
references: Expert Opin Biol Ther. 2008 Jun;8(6):719-24
references: 18476783
references: Trends Microbiol. 2008 Aug;16(8):361-9
references: 18585915
references: Eur J Clin Microbiol Infect Dis. 2008 Sep;27(9):839-48
references: 18449584
references: Annu Rev Genet. 2008;42:541-64
references: 18713030
references: Antimicrob Agents Chemother. 2009 Feb;53(2):580-6
references: 19015326
references: Proc Natl Acad Sci U S A. 2009 Jan 27;106(4):1216-21
references: 19147840
references: Plasmid. 2009 Mar;61(2):126-9
references: 18996145
references: J Microbiol Methods. 2009 Jun;77(3):251-60
references: 19264102
references: Clin Exp Immunol. 2009 Aug;157(2):216-24
references: 19604261
references: FEMS Microbiol Lett. 2009 Jun;295(2):204-10
references: 19459979
references: J Immunol. 2009 Sep 15;183(6):3942-8
references: 19717510
references: PLoS One. 2009;4(10):e7446
references: 19826485
references: J Comput Chem. 2010 Jan 30;31(2):455-61
references: 19499576
references: Appl Environ Microbiol. 2010 Jan;76(1):150-60
references: 19880638
references: EMBO Mol Med. 2009 Jul;1(4):201-10
references: 20049722
references: Nat Rev Drug Discov. 2010 Feb;9(2):117-28
references: 20081869
references: J Infect Dis. 2010 Oct 1;202(7):1050-8
references: 20726702
references: J Innate Immun. 2010;2(6):546-59
references: 20829608
references: J Infect Dis. 2010 Nov 15;202(10):1593-9
references: 20942648
references: J Nat Prod. 2012 Mar 23;75(3):311-35
references: 22316239
references: PLoS One. 2012;7(5):e36532
references: 22574180
references: Semin Immunopathol. 2015 Jan;37(1):73-80
references: 25326105
references: Nucleic Acids Res. 2000 Jan 1;28(1):235-42
references: 10592235
references: J Immunol. 2000 Apr 1;164(7):3713-22
references: 10725730
references: Infect Immun. 2001 Mar;69(3):1957-60
references: 11179383
references: J Bacteriol. 2001 Dec;183(24):7341-53
references: 11717293
references: Infect Immun. 2002 Feb;70(2):631-41
references: 11796592
references: Appl Environ Microbiol. 2003 Jan;69(1):18-23
references: 12513972
references: J Immunol. 2003 Nov 15;171(10):5389-95
references: 14607942
references: Proc Natl Acad Sci U S A. 2004 Sep 21;101(38):13867-72
references: 15353593
references: Cancer Res. 1988 Sep 1;48(17):4827-33
references: 3409223
references: Methods Enzymol. 1988;165:213-7
references: 2906728