Nitazoxanide inhibits biofilm formation by Staphylococcus epidermidis by blocking accumulation on surfaces.
Coagulase-negative species of Staphylococcus are often associated with opportunistic hospital-acquired infections that arise from the colonization of indwelling catheters. Here we show that the antiparasitic drug nitazoxanide (NTZ) and its active metabolite, tizoxanide (TIZ), are inhibitory to the growth of Staphylococcus epidermidis and other staphylococci, including methicillin-resistant Staphylococcus aureus strains, under aerobic and microaerobic conditions (MICs, 8 to 16 microg/ml). At sub-MIC levels, NTZ and TIZ also inhibited biofilm production under static conditions by strains of S. epidermidis and Staphylococcus haemolyticus with a 50% inhibitory concentration of approximately 2.5 microg/ml (8 microM). The 5-nitro group was required for biological activity, and a hydrophilic derivative of NTZ (AMIX) also inhibited biofilm formation. NTZ did not disperse the existing biofilm but did block further accumulation. Sub-MICs of NTZ had no effect on primary attachment to surfaces at either 4 or 37 degrees C. The inhibitory action of NTZ and TIZ, but not vancomycin, on biofilm production could be reversed by the addition of zinc salts (2.5 to 40 microM) but not other metals, suggesting that NTZ might target the zinc-dependent accumulation-associated protein (Aap) that mediates accumulation on surfaces. However, neither NTZ nor TIZ formed chelation complexes with zinc salts, based on spectrophotometric and nuclear magnetic resonance analyses, and addition of excess zinc to NTZ-grown bacteria (apo-Aap) did not restore the accumulation phenotype. Our studies suggest that sub-MIC levels of NTZ may affect the assembly or function of cell structures associated with the biofilm phenotype.
Tchouaffi-Nana
Florence
F
Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, VA 22908-0734, USA.
Ballard
T Eric
TE
Cary
Christine H
CH
Macdonald
Timothy L
TL
Sifri
Costi D
CD
Hoffman
Paul S
PS
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D018441:Biofilms / Q000187:drug effects*; D009682:Magnetic Resonance Spectroscopy; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009574:Nitro Compounds; D013212:Staphylococcus epidermidis / Q000187:drug effects*; D013844:Thiazoles / Q000494:pharmacology*; D014640:Vancomycin / Q000494:pharmacology; D015032:Zinc / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D009574:Nitro Compounds; D013844:Thiazoles; C104067:tizoxanide; D014640:Vancomycin; D015032:Zinc; C041747:nitazoxanide
Microbes Infect. 2002 Apr;4(4):481-9
11932199
Antimicrob Agents Chemother. 2007 Mar;51(3):868-76
17158936
Microbiology (Reading). 2007 Aug;153(Pt 8):2435-2446
17660408
J Bacteriol. 1996 Jan;178(1):175-83
8550413
Antimicrob Agents Chemother. 1996 Oct;40(10):2266-70
8891127
Antimicrob Agents Chemother. 2007 Apr;51(4):1556-8
17220399
Expert Opin Pharmacother. 2006 May;7(7):953-64
16634717
Antimicrob Agents Chemother. 2010 Apr;54(4):1526-33
20086145
J Microbiol Methods. 2003 Nov;55(2):465-9
14529969
Antimicrob Agents Chemother. 2006 Mar;50(3):1112-7
16495282
Ann Intern Med. 1997 Aug 15;127(4):257-66
9265424
Am J Infect Control. 2004 Dec;32(8):470-85
15573054
Infect Immun. 1997 Feb;65(2):519-24
9009307
Antimicrob Agents Chemother. 2002 Jul;46(7):2116-23
12069963
Ann Intern Med. 2000 Mar 7;132(5):391-402
10691590
Appl Environ Microbiol. 2005 Dec;71(12):8677-82
16332862
Antimicrob Agents Chemother. 2000 Sep;44(9):2254-8
10952564
Lett Appl Microbiol. 2006 Sep;43(3):325-30
16910940
Org Biomol Chem. 2009 Feb 21;7(4):794-802
19194596
Mol Microbiol. 2005 Mar;55(6):1883-95
15752207
Lancet Infect Dis. 2002 Nov;2(11):677-85
12409048
Mol Microbiol. 1996 Jun;20(5):1083-91
8809760
Infect Immun. 1994 Aug;62(8):3244-53
8039894
Antimicrob Agents Chemother. 2007 Jun;51(6):1979-86
17438059
Chemotherapy. 1999 Jul-Aug;45(4):303-12
10394014
PLoS Pathog. 2007 Apr;3(4):e57
17447841
Int J Clin Pharmacol Ther. 1996 Aug;34(8):349-51
8864798
Ann Agric Environ Med. 2008;15(2):237-41
19118444
Proc Natl Acad Sci U S A. 2008 Dec 9;105(49):19456-61
19047636
Int J Cancer. 2008 Oct 15;123(8):1797-806
18688861
Infect Immun. 1999 May;67(5):2656-9
10225938
Clin Infect Dis. 2009 Feb 15;48(4):e41-6
19133801
Public Health Rep. 2007 Mar-Apr;122(2):160-6
17357358
Am J Med. 2008 Oct;121(10):855-7
18823853
Infect Immun. 1992 May;60(5):2048-57
1314224
Annu Rev Microbiol. 2003;57:677-701
14527295
J Clin Microbiol. 2001 Jul;39(7):2541-7
11427566