c-di-GMP (3'-5'-cyclic diguanylic acid) inhibits Staphylococcus aureus cell-cell interactions and biofilm formation.
Staphylococcus aureus is an important pathogen of humans and animals, and antibiotic resistance is a public health concern. Biofilm formation is essential in virulence and pathogenesis, and the ability to resist antibiotic treatment results in difficult-to-treat and persistent infections. As such, novel antimicrobial approaches are of great interest to the scientific, medical, and agriculture communities. We recently proposed that modulating levels of the cyclic dinucleotide signaling molecule, c-di-GMP (cyclic diguanylate [3',5'-cyclic diguanylic acid], cGpGp), has utility in regulating phenotypes of prokaryotes. We report that extracellular c-di-GMP shows activity against human clinical and bovine intramammary mastitis isolates of S. aureus, including methicillin-resistant S. aureus (MRSA) isolates. We show that chemically synthesized c-di-GMP is soluble and stable in water and physiological saline and stable following boiling and exposure to acid and alkali. Treatment of S. aureus with extracellular c-di-GMP inhibited cell-to-cell (intercellular) adhesive interactions in liquid medium and reduced (>50%) biofilm formation in human and bovine isolates compared to untreated controls. c-di-GMP inhibited the adherence of S. aureus to human epithelial HeLa cells. The cyclic nucleotide analogs cyclic GMP and cyclic AMP had a lesser inhibitory effect on biofilms, while 5'-GMP had no major effect. We propose that cyclic dinucleotides such as c-di-GMP, used either alone or in combination with other antimicrobial agents, represent a novel and attractive approach in the development of intervention strategies for the prevention of biofilms and the control and treatment of infection.
Karaolis
David K R
DK
Department of Epidemiology and Preventive Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA. karaolis@umaryland.edu
Rashid
Mohammed H
MH
Chythanya
Rajanna
R
Luo
Wensheng
W
Hyodo
Mamoru
M
Hayakawa
Yoshihiro
Y
D000818:Animals; D001422:Bacterial Adhesion / Q000187:drug effects; D018441:Biofilms / Q000187:drug effects*; D002417:Cattle; D002851:Chromatography, High Pressure Liquid; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004492:Edetic Acid / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000502:physiology
C062025:bis(3',5')-cyclic diguanylic acid; D004492:Edetic Acid; D006152:Cyclic GMP
Ann Intern Med. 1991 Jan 15;114(2):107-12
1984384
Am J Infect Control. 1998 Oct;26(5):522-33
9795682
J Bacteriol. 2002 Dec;184(23):6481-9
12426335
Infect Control Hosp Epidemiol. 2003 May;24(5):362-86
12785411
Ann Intern Med. 1991 Sep 15;115(6):417-22
1908198
FEBS Lett. 1999 Feb 5;444(1):125-9
10037160
Res Microbiol. 2002 May;153(4):205-12
12066891
Anesth Analg. 1994 Apr;78(4):644-50
8135381
N Engl J Med. 1986 Jul 10;315(2):91-6
3523240
Clin Diagn Lab Immunol. 2001 Nov;8(6):1064-9
11687441
J Bacteriol. 2001 May;183(9):2888-96
11292810
Clin Infect Dis. 1998 May;26(5):1179-81
9597249
J Infect Dis. 1974 Jun;129(6):725-7
4834284
FEMS Microbiol Lett. 2003 Oct 10;227(1):113-9
14568156
Proc Natl Acad Sci U S A. 1991 Jun 15;88(12):5472-6
1647035
Ann Intern Med. 1999 Feb 2;130(3):221-5
10049200
Infect Control Hosp Epidemiol. 1994 Feb;15(2):78-81
8201238
J Bacteriol. 2002 Jun;184(12):3406-10
12029060
JAMA. 1975 Mar 24;231(12):1272
1172956
Am J Med. 1996 May;100(5):509-16
8644762
Microbiology. 2000 Dec;146 Pt 12:3183-94
11101676
Mol Microbiol. 2004 Aug;53(4):1123-34
15306016
J Hosp Infect. 2001 Feb;47(2):98-103
11170772
Environ Microbiol. 2004 Jun;6(6):552-67
15142243
Mol Microbiol. 2002 Mar;43(6):1367-78
11952892
Infect Immun. 1999 Oct;67(10):5427-33
10496925
Mol Microbiol. 2000 Apr;36(1):10-23
10760159
Clin Infect Dis. 2003 Feb 1;36(3):281-5
12539068
Infect Immun. 2002 Feb;70(2):470-80
11796572
J Biol Chem. 1990 Nov 5;265(31):18933-43
2172238
Infect Immun. 2002 Aug;70(8):4433-40
12117954
Microbiol Rev. 1991 Mar;55(1):35-58
2030672
Nucleic Acids Res. 2001 Jan 1;29(1):22-8
11125040
Mol Microbiol. 2003 May;48(4):1075-87
12753197
J Antimicrob Chemother. 1989 Jan;23(1):79-86
2775357
FEMS Microbiol Lett. 2001 Sep 11;203(1):11-21
11557134
J Bacteriol. 2000 Jul;182(13):3839-42
10851002
Clin Microbiol Rev. 1997 Jul;10(3):505-20
9227864
Genes Dev. 2004 Mar 15;18(6):715-27
15075296
Curr Opin Microbiol. 2004 Apr;7(2):185-91
15063857
Arch Intern Med. 1978 Nov;138(11):1657-9
718314
Kidney Int. 2003 Jan;63(1):340-5
12472801
Microbiol Immunol. 1996;40(4):247-54
8709859
Infect Immun. 2003 Jul;71(7):4206-11
12819120
J Med Microbiol. 1994 Feb;40(2):79-89
8107066
Infect Immun. 2004 Apr;72(4):2177-85
15039341
Microbiology. 2003 Oct;149(Pt 10):2759-67
14523109
Clin Infect Dis. 2003 Jan 1;36(1):53-9
12491202
Science. 1999 May 28;284(5419):1523-7
10348739
Microbiology. 1997 Jun;143 ( Pt 6):1909-18
9202467
J Bacteriol. 2003 Feb;185(4):1384-90
12562809
J Antimicrob Chemother. 1991 Dec;28(6):811-7
1816179
FEMS Microbiol Lett. 2001 Oct 16;204(1):163-7
11682196
N Engl J Med. 2001 Jan 4;344(1):11-6
11136954
Microbiology. 1999 Aug;145 ( Pt 8):2117-28
10463178
J Appl Bacteriol. 1990 Dec;69(6):834-44
2286582
J Bacteriol. 1989 Dec;171(12):6649-55
2556370
N Engl J Med. 1990 Feb 22;322(8):505-9
2300122
Trends Microbiol. 2001 Dec;9(12):605-10
11728874
Infect Immun. 2002 Jun;70(6):3180-6
12011013
Vet Microbiol. 2003 Jan 2;91(1):57-64
12441231
FEBS Lett. 1985 Jul 8;186(2):191-6
19160595