Subinhibitory Concentrations of Linezolid Reduce
            <i>Staphylococcus aureus</i>
            Virulence Factor Expression

Bernardo, Katussevani; Pakulat, Norbert; Fleer, Silke; Schnaith, Annabelle; Utermöhlen, Olaf; Krut, Oleg; Müller, Stefan; Krönke, Martin

doi:10.1128/aac.48.2.546-555.2004

Cited by 195 publications

(149 citation statements)

References 45 publications

Supporting

Mentioning

137

Contrasting

Unclassified

Order By: Relevance

“…All these proteins were dramatically decreased in MRSA exposed to TPP. These results are reminiscent of those reported by Bernardo et al [2], who found that sub-MIC levels of linezolid reduced the expression of various S. aureus virulence factors. While the synergistic mechanism of TPP for enhanced killing of MRSA by oxacillin is still unclear, these data demonstrate that sub-MIC exposure to TPP dramatically affects the expression of several important proteins in MRSA.…”

Section: Resultssupporting

confidence: 65%

See 1 more Smart Citation

Antibacterial Effects of Green Tea Polyphenols on Clinical Isolates of Methicillin-Resistant Staphylococcus aureus

Cho

Schiller

2008

Curr Microbiol

View full text Add to dashboard Cite

The antibacterial effects of tea polyphenols (TPP) extracted from Korean green tea (Camellia sinensis) against clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) were evaluated. Characterization of the minimal inhibitory concentration (MIC) of oxacillin for 30 S. aureus strains isolated from patients treated with oxacillin identified 13 strains with an oxacillin MIC C 4 lg/mL as methicillinresistant Staphylococcus aureus (MRSA) (range: 8 to 512 lg/ mL), while 17 strains were methicillin-susceptible Staphylococcus aureus (MSSA) (range: 0.25-0.5 lg/mL). The MICs of TPP ranged from 50 to 180 lg/mL for both the MSSA and the MRSA strains. The MICs of oxacillin for each of the 13 MRSA strains were reduced between 8-and 128-fold when these strains were coincubated with sub-MIC (B0.59 MIC) levels of TPP, demonstrating that the combination of TPP plus oxacillin was synergistic for all of the clinical MRSA isolates. Two-dimensional polyacrylamide gel electrophoresis identified 14 extracellular proteins of MRSA-13 down-regulated and 3 proteins up-regulated by exposure to TPP. These studies demonstrate that TPP can differentially stimulate the expression of various proteins in these bacteria and synergize the bactericidal activity of oxacillin for MRSA.

show abstract

Section: Resultssupporting

confidence: 65%

“…Proteins in the culture supernatants were precipitated by the addition of 100% trichloroacetic acid to a final concentration of 10%. After overnight incubation at 4°C, the precipitate was centrifuged at 10,000 g for 30 min at 4°C and washed with ice-cold 100% acetone [1,2]. 2-DE was performed according to previously described methods [9].…”

Section: Methodsmentioning

confidence: 99%

Antibacterial Effects of Green Tea Polyphenols on Clinical Isolates of Methicillin-Resistant Staphylococcus aureus

Cho

Schiller

2008

Curr Microbiol

View full text Add to dashboard Cite

show abstract

“…This is an important factor to consider, because the antibiotic used could have a direct impact on virulence factor expression, including alpha-toxin. For example, studies have demonstrated that protein synthesis inhibitor antibiotics suppress expression of virulence factors like TSST-1, alpha-toxin, and coagulase in S. aureus isolates (59)(60)(61), while the cell wall-acting antibiotics have either no effect or enhance production of extracellular virulence factors (44,62). Second, the matched S. aureus isolates and serum samples were collected only after the subjects had experienced clinical symptoms for several days (average of 2 days [range, 0 to 30 days]) and had presented to the attending physician.…”

Section: Figmentioning

confidence: 99%

Characterization of Alpha-Toxin hla Gene Variants, Alpha-Toxin Expression Levels, and Levels of Antibody to Alpha-Toxin in Hemodialysis and Postsurgical Patients with Staphylococcus aureus Bacteremia

Sharma-Kuinkel

Wu²,

Tabor³

et al. 2015

J Clin Microbiol

View full text Add to dashboard Cite

c Alpha-toxin is a major Staphylococcus aureus virulence factor. This study evaluated potential relationships between in vitro alpha-toxin expression of S. aureus bloodstream isolates, anti-alpha-toxin antibody in serum of patients with S. aureus bacteremia (SAB), and clinical outcomes in 100 hemodialysis and 100 postsurgical SAB patients. Isolates underwent spa typing and hla sequencing. Serum anti-alpha-toxin IgG and neutralizing antibody levels were measured by using an enzyme-linked immunosorbent assay and a red blood cell (RBC)-based hemolysis neutralization assay. Neutralization of alpha-toxin by an anti-alpha-toxin monoclonal antibody (MAb MEDI4893) was tested in an RBC-based lysis assay. Most isolates encoded hla (197/200; 98.5%) and expressed alpha-toxin (173/200; 86.5%). In vitro alpha-toxin levels were inversely associated with survival (cure, 2.19 g/ml, versus failure, 1.09 g/ml; P < 0.01). Both neutralizing (hemodialysis, 1.26 IU/ml, versus postsurgical, 0.95; P < 0.05) and IgG (hemodialysis, 1.94 IU/ml, versus postsurgical, 1.27; P < 0.05) antibody levels were higher in the hemodialysis population. Antibody levels were also significantly higher in patients infected with alpha-toxin-expressing S. aureus isolates (P < 0.05). Levels of both neutralizing antibodies and IgG were similar among patients who were cured and those not cured (failures). Sequence analysis of hla revealed 12 distinct hla genotypes, and all genotypic variants were susceptible to a neutralizing monoclonal antibody in clinical development (MEDI4893). These data demonstrate that alpha-toxin is highly conserved in clinical S. aureus isolates. Higher in vitro alpha-toxin levels were associated with a positive clinical outcome. Although patients infected with alpha-toxin-producing S. aureus exhibited higher anti-alpha-toxin antibody levels, these levels were not associated with a better clinical outcome in this study. Staphylococcus aureus is a leading cause of bacterial infections (1-4), including skin and soft tissue infections (5), pneumonia (6), bacteremia (7), endocarditis (8-10), and bone and joint infections (11). The risk of invasive S. aureus infections is significantly higher among certain subgroups, including hemodialysisdependent patients and postoperative patients (12-14).These high-risk subpopulations are potential candidates for novel forms of prevention or treatment against invasive S. aureus infections.Alpha-toxin, a ␤-barrel pore-forming exotoxin encoded by hla (15, 16), is a key virulence factor produced by most S. aureus isolates (17, 18). It binds to ADAM10 (the A disintegrin and metalloproteinase domain-containing protein 10) on target cell membranes and then heptamerizes to generate a transmembrane pore, resulting in cell lysis (19). Hyperproduction of alpha-toxin is associated with enhanced virulence in strains of both epidemic (USA300 and USA500) and endemic (ST93) community-associated methicillin-resistant S. aureus (CA-MRSA) isolates (20,21). Studies with a number of animal models have also suggested that al...

show abstract

“…This effect has been shown when pathogens are exposed to subinhibitory concentrations of antibiotics. For instance, subinhibitory concentrations of clindamycin and linezolid have the ability to downregulate the expression of Staphylococcus aureus exotoxins, including a-haemolysin (hla) (Herbert et al, 2001;Bernardo et al, 2004). In contrast, subinhibitory concentrations of the cell-wall-acting b-lactam antibiotics have been shown to induce the expression of hla (Ohlsen et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Amphibian antimicrobial peptide fallaxin analogue FL9 affects virulence gene expression and DNA replication in Staphylococcus aureus

Gottschalk

Gottlieb

Vestergaard

et al. 2015

Journal of Medical Microbiology

View full text Add to dashboard Cite

The rapid rise in antibiotic-resistant pathogens is causing increased health concerns, and consequently there is an urgent need for novel antimicrobial agents. Antimicrobial peptides (AMPs), which have been isolated from a wide range of organisms, represent a very promising class of novel antimicrobials. In the present study, the analogue FL9, based on the amphibian AMP fallaxin, was studied to elucidate its mode of action and antibacterial activity against the human pathogen Staphylococcus aureus. Our data showed that FL9 may have a dual mode of action against S. aureus. At concentrations around the MIC, FL9 bound DNA, inhibited DNA synthesis and induced the SOS DNA damage response, whereas at concentrations above the MIC the interaction between S. aureus and FL9 led to membrane disruption. The antibacterial activity of the peptide was maintained over a wide range of NaCl and MgCl 2 concentrations and at alkaline pH, while it was compromised by acidic pH and exposure to serum. Furthermore, at subinhibitory concentrations of FL9, S. aureus responded by increasing the expression of two major virulence factor genes, namely the regulatory rnaIII and hla, encoding a-haemolysin. In addition, the S. aureus-encoded natural tolerance mechanisms included peptide cleavage and the addition of positive charge to the cell surface, both of which minimized the antimicrobial activity of FL9. Our results add new information about FL9 and its effect on S. aureus, which may aid in the future development of analogues with improved therapeutic potential.

show abstract

Subinhibitory Concentrations of Linezolid Reduce Staphylococcus aureus Virulence Factor Expression

Cited by 195 publications

References 45 publications

Antibacterial Effects of Green Tea Polyphenols on Clinical Isolates of Methicillin-Resistant Staphylococcus aureus

Antibacterial Effects of Green Tea Polyphenols on Clinical Isolates of Methicillin-Resistant Staphylococcus aureus

Characterization of Alpha-Toxin hla Gene Variants, Alpha-Toxin Expression Levels, and Levels of Antibody to Alpha-Toxin in Hemodialysis and Postsurgical Patients with Staphylococcus aureus Bacteremia

Amphibian antimicrobial peptide fallaxin analogue FL9 affects virulence gene expression and DNA replication in Staphylococcus aureus

Contact Info

Product

Resources

About