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Nitazoxanide inhibits biofilm formation by Staphylococcus epidermidis by blocking accumulation on surfaces.

ABSTRACT: 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.

SUBMITTER: Tchouaffi-Nana F

PROVIDER: S-EPMC2897279 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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Nitazoxanide inhibits biofilm formation by Staphylococcus epidermidis by blocking accumulation on surfaces.

Tchouaffi-Nana Florence F Ballard T Eric TE Cary Christine H CH Macdonald Timothy L TL Sifri Costi D CD Hoffman Paul S PS

Antimicrobial agents and chemotherapy 20100419 7

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- ...[more]

PMID: 20404119

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Project description:The role of material surface properties in the direct interaction with bacteria and the indirect route via host defense cells is not fully understood. Recently, it was suggested that nanostructured implant surfaces possess antimicrobial properties. In the current study, the adhesion and biofilm formation of Staphylococcus epidermidis and human monocyte adhesion and activation were studied separately and in coculture in different in vitro models using smooth gold and well-defined nanostructured gold surfaces. Two polystyrene surfaces were used as controls in the monocyte experiments. Fluorescent viability staining demonstrated a reduction in the viability of S. epidermidis close to the nanostructured gold surface, whereas the smooth gold correlated with more live biofilm. The results were supported by scanning electron microscopy observations, showing higher biofilm tower formations and more mature biofilms on smooth gold compared with nanostructured gold. Unstimulated monocytes on the different substrates demonstrated low activation, reduced gene expression of pro- and anti-inflammatory cytokines, and low cytokine secretion. In contrast, stimulation with opsonized zymosan or opsonized live S. epidermidis for 1 hour significantly increased the production of reactive oxygen species, the gene expression of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, and IL-10, as well as the secretion of TNF-α, demonstrating the ability of the cells to elicit a response and actively phagocytose prey. In addition, cells cultured on the smooth gold and the nanostructured gold displayed a different adhesion pattern and a more rapid oxidative burst than those cultured on polystyrene upon stimulation. We conclude that S. epidermidis decreased its viability initially when adhering to nanostructured surfaces compared with smooth gold surfaces, especially in the bacterial cell layers closest to the surface. In contrast, material surface properties neither strongly promoted nor attenuated the activity of monocytes when exposed to zymosan particles or S. epidermidis.

Project description:Staphylococcus epidermidis is part of the normal microbiota that colonizes the skin and mucosal surfaces of human beings. Previous studies suggested that S. epidermidis possessed low virulence, but recent studies confirmed that it can acquire high virulence from Staphylococcus aureus and with the increasing detection of methicillin-resistant S. epidermidis. It has become a major pathogen of graft-associated and hospital-acquired infections. In previous studies, we modified the antimicrobial peptide Cec4 (41 amino acids) and obtained the derived peptide C9 (16 amino acids) showing better antimicrobial activity against S. epidermidis with an MIC value of 8 μg/mL. The peptide has rapid bactericidal activity without detectable high-level resistance, showing certain inhibition and eradication ability on S. epidermidis biofilms. The damage of cell membrane structures by C9 was observed by scanning emission microscopy (SEM) and transmission electron microscopy (TEM). In addition, C9 altered the S. epidermidis cell membrane permeability, depolarization levels, fluidity, and reactive oxygen species (ROS) accumulation and possessed the ability to bind genomic DNA. Analysis of the transcriptional profiles of C9-treated cells revealed changes in genes involved in cell wall and ribosome biosynthesis, membrane protein transport, oxidative stress, and DNA transcription regulation. At the same time, the median lethal dose of C9 in mice was more than 128 mg/kg, and the intraperitoneal administration of 64 mg/kg was less toxic to the liver and kidneys of mice. Furthermore, C9 also showed a certain therapeutic effect on the mouse bacteremia model. In conclusion, C9 may be a candidate drug against S. epidermidis, which has the potential to be further developed as an antibacterial therapeutic agent. IMPORTANCE S. epidermidis is one of the most important pathogens of graft-related infection and hospital-acquired infection. The growing problem of antibiotic resistance, as well as the emergence of bacterial pathogenicity, highlights the need for antimicrobials with new modes of action. Antimicrobial peptides have been extensively studied over the past 30 years as ideal alternatives to antibiotics, and we report here that the derived peptide C9 is characterized by rapid bactericidal and antibiofilm activity, avoiding the development of resistance by acting on multiple nonspecific targets of the cell membrane or cell components. In addition, it has therapeutic potential against S. epidermidis infection in vivo. This study provides a rationale for the further development and application of C9 as an effective candidate antibiotic.

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Nitazoxanide inhibits biofilm formation by Staphylococcus epidermidis by blocking accumulation on surfaces.

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Nitazoxanide inhibits biofilm formation by Staphylococcus epidermidis by blocking accumulation on surfaces.

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