title: A novel nitro-dexamethasone inhibits agr system activity and improves therapeutic effects in MRSA sepsis models without antibiotics.
abstract: Methicillin-resistant Staphylococcus aureus (MRSA) sepsis is a life-threatening medical condition that involves systemic inflammation throughout the body. Glucocorticoids are widely used in combination with antibiotics in the treatment of MRSA sepsis to fight the overwhelming inflammation. Here, we describe the improved anti-inflammatory properties of a nitric oxide (NO)-releasing derivative of dexamethasone, ND8008. ND8008 affected MRSA biofilm formation, caused biofilm cell death, and reduced the effects of virulence factors, such as α-toxin, by inhibiting the activity of the Staphylococcus aureus accessory gene regulator (agr) system. Dosing of mice with ND8008 (127.4 nmol/kg, i.p.) alone greatly reduced the inflammatory response caused by MRSA blood stream infection and considerably increased the survival rate of septic mice. These findings suggest that this novel NO-releasing derivative of dexamethasone ND8008 could be helpful in the treatment of MRSA sepsis.
authors.affiliation: National Engineering Research Center of Immunological Products &Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical University, Chongqing 400038, PR China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, Third Military Medical University, Chongqing 400038, PR China.
authors.forename: Haibo
authors.initials: H
authors.lastname: Li
authors.affiliation: National Engineering Research Center of Immunological Products &Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical University, Chongqing 400038, PR China.
authors.forename: Hongwu
authors.initials: H
authors.lastname: Sun
authors.affiliation: National Engineering Research Center of Immunological Products &Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical University, Chongqing 400038, PR China.
authors.forename: Li
authors.initials: L
authors.lastname: Gong
authors.affiliation: Institute of Immunology of PLA, Third Military Medical University, Chongqing 400038, PR China.
authors.forename: Ling
authors.initials: L
authors.lastname: Guo
authors.affiliation: National Engineering Research Center of Immunological Products &Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical University, Chongqing 400038, PR China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Shi
authors.affiliation: National Engineering Research Center of Immunological Products &Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical University, Chongqing 400038, PR China.
authors.forename: Changzhi
authors.initials: C
authors.lastname: Cai
authors.affiliation: National Engineering Research Center of Immunological Products &Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical University, Chongqing 400038, PR China.
authors.forename: Hao
authors.initials: H
authors.lastname: Gu
authors.affiliation: National Engineering Research Center of Immunological Products &Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical University, Chongqing 400038, PR China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Song
authors.affiliation: National Engineering Research Center of Immunological Products &Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical University, Chongqing 400038, PR China.
authors.forename: Liuyang
authors.initials: L
authors.lastname: Yang
authors.affiliation: National Engineering Research Center of Immunological Products &Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical University, Chongqing 400038, PR China.
authors.forename: Yanan
authors.initials: Y
authors.lastname: Tong
authors.affiliation: National Engineering Research Center of Immunological Products &Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical University, Chongqing 400038, PR China.
authors.forename: Chao
authors.initials: C
authors.lastname: Wei
authors.affiliation: National Engineering Research Center of Immunological Products &Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical University, Chongqing 400038, PR China.
authors.forename: Quanming
authors.initials: Q
authors.lastname: Zou
authors.affiliation: National Engineering Research Center of Immunological Products &Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical University, Chongqing 400038, PR China.
authors.forename: Hao
authors.initials: H
authors.lastname: Zeng
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D001426:Bacterial Proteins / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003907:Dexamethasone / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D004195:Disease Models, Animal; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects; D008264:Macrophages; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009566:Nitrates / Q000008:administration & dosage* / Q000494:pharmacology; D009569:Nitric Oxide / Q000737:chemistry*; D018805:Sepsis / Q000188:drug therapy* / Q000276:immunology; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000276:immunology; D015534:Trans-Activators / Q000187:drug effects
chemical_list: C095698:Agr protein, Staphylococcus aureus; D000893:Anti-Inflammatory Agents; D001426:Bacterial Proteins; D016207:Cytokines; C000613421:ND8008; D009566:Nitrates; D015534:Trans-Activators; D009569:Nitric Oxide; D003907:Dexamethasone
references.citation: Cell Res. 2013 Feb;23(2):201-12
references.pmid: 23318584
references.citation: Ann Intensive Care. 2011 Apr 13;1(1):7
references.pmid: 21906332
references.citation: Intensive Care Med. 2005 Jan;31(1):146-50
references.pmid: 15502933
references.citation: Mol Pharm. 2015 May 4;12(5):1573-83
references.pmid: 25873449
references.citation: Br J Pharmacol. 2000 Dec;131(7):1345-54
references.pmid: 11090106
references.citation: Cell Host Microbe. 2015 Jun 10;17(6):775-87
references.pmid: 26067604
references.citation: Antimicrob Agents Chemother. 2012 Dec;56(12):6095-103
references.pmid: 22948868
references.citation: Infect Immun. 1997 May;65(5):1870-5
references.pmid: 9125574
references.citation: Br J Pharmacol. 2007 Oct;152(4):421-8
references.pmid: 17641669
references.citation: Proc Natl Acad Sci U S A. 2000 Dec 19;97(26):14602-7
references.pmid: 11121062
references.citation: Microb Pathog. 2008 Jul;45(1):45-52
references.pmid: 18479885
references.citation: J Infect. 2013 Dec;67(6):574-83
references.pmid: 23933016
references.citation: J Antibiot (Tokyo). 2015 Jan;68(1):15-22
references.pmid: 25074658
references.citation: J Infect. 2014 Aug;69(2):113-22
references.pmid: 24657243
references.citation: Proc Natl Acad Sci U S A. 2002 Feb 5;99(3):1677-82
references.pmid: 11805287
references.citation: Infect Immun. 1999 Oct;67(10):5427-33
references.pmid: 10496925
references.citation: J Invest Dermatol. 2009 Oct;129(10):2463-9
references.pmid: 19387479
references.citation: Arthritis Rheum. 1996 Sep;39(9):1596-605
references.pmid: 8814072
references.citation: Microbiology. 2008 Nov;154(Pt 11):3480-90
references.pmid: 18957601
references.citation: PLoS Pathog. 2008 Apr;4(4):e1000052
references.pmid: 18437240
references.citation: J Bacteriol. 2010 Nov;192(22):6077-85
references.pmid: 20870770
references.citation: Biochem Pharmacol. 2005 Jul 15;70(2):209-19
references.pmid: 15935330
references.citation: Antimicrob Agents Chemother. 2011 Dec;55(12):5631-9
references.pmid: 21968365
references.citation: Antimicrob Agents Chemother. 2011 Feb;55(2):860-6
references.pmid: 21135178
references.citation: Infect Immun. 1997 Jul;65(7):2517-21
references.pmid: 9199413
references.citation: Nitric Oxide. 2015 Sep 15;49:8-15
references.pmid: 26028569
references.citation: Infect Immun. 2003 Jul;71(7):4206-11
references.pmid: 12819120
references.citation: J Infect Dis. 2003 Feb 15;187(4):625-30
references.pmid: 12599079
references.citation: Eur Heart J. 2014 Apr;35(14):888-94
references.pmid: 24357508
references.citation: Br J Pharmacol. 2003 Sep;140(1):91-6
references.pmid: 12967938
references.citation: Br J Ophthalmol. 2006 Nov;90(11):1414-9
references.pmid: 16914472
references.citation: PLoS One. 2014;9(3):e92117
references.pmid: 24658315
references.citation: Mol Microbiol. 2001 Jun;40(6):1439-47
references.pmid: 11442841
references.citation: J Infect Dis. 1997 Feb;175(2):462-6
references.pmid: 9203674
references.citation: Biochem Soc Trans. 2007 Nov;35(Pt 5):1364-8
references.pmid: 17956352
references.citation: Chem Soc Rev. 2014 Oct 7;43(19):6814-38
references.pmid: 24549364
references.citation: Antimicrob Agents Chemother. 1991 Jul;35(7):1298-302
references.pmid: 1929285
references.citation: Free Radic Biol Med. 2014 Dec;77:307-16
references.pmid: 25229185
references.citation: Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8496-501
references.pmid: 12829799
references.citation: Adv Drug Deliv Rev. 2013 Nov;65(13-14):1803-15
references.pmid: 23892192
references.citation: Cell Host Microbe. 2014 Oct 8;16(4):531-7
references.pmid: 25299336
references.citation: Laryngoscope. 2014 Mar;124(3):602-7
references.pmid: 23878015
references.citation: Crit Care. 2010;14(4):R134
references.pmid: 20626892
references.citation: J Bacteriol. 2003 May;185(10):3214-7
references.pmid: 12730182
references.citation: N Engl J Med. 2005 Oct 20;353(16):1711-23
references.pmid: 16236742
references.citation: Int Forum Allergy Rhinol. 2011 Nov-Dec;1(6):438-44
references.pmid: 22144052
references.citation: Peptides. 2001 Oct;22(10):1621-7
references.pmid: 11587790
references.citation: Antimicrob Agents Chemother. 2007 Dec;51(12):4518-20
references.pmid: 17875996
references.citation: Antimicrob Agents Chemother. 2001 Dec;45(12):3531-7
references.pmid: 11709335
references.citation: Mol Cell. 2008 Oct 10;32(1):150-8
references.pmid: 18851841
references.citation: Genes Dev. 2003 Jan 1;17(1):115-25
references.pmid: 12514104