Impact of sub-inhibitory antibiotics on fibronectin-mediated host cell adhesion and invasion by Staphylococcus aureus

Abstract

BackgroundStaphylococcus aureus is a well-armed pathogen prevalent in severe infections such as endocarditis and osteomyelitis. Fibronectin-binding proteins A and B, encoded by fnbA/B, are major pathogenesis determinants in these infections through their involvement in S. aureus adhesion to and invasion of host cells. Sub-minimum inhibitory concentrations (sub-MICs) of antibiotics, frequently occurring in vivo because of impaired drug diffusion at the infection site, can alter S. aureus phenotype. We therefore investigated their impact on S. aureus fibronectin-mediated adhesiveness and invasiveness.MethodsAfter in vitro challenge of S. aureus 8325-4 and clinical isolates with sub-MICs of major anti-staphylococcal agents, we explored fnbA/B transcription levels, bacterial adhesiveness to immobilised human fibronectin and human osteoblasts in culture, and bacterial invasion of human osteoblasts.ResultsOxacillin, moxifloxacin and linezolid led to the development of a hyper-adhesive phenotype in the fibronectin adhesion assay that was consistent with an increase in fnbA/B transcription. Conversely, rifampin treatment decreased fibronectin binding in all strains tested without affecting fnbA/B transcription. Gentamicin and vancomycin had no impact on fibronectin binding or fnbA/B transcription levels. Only oxacillin-treated S. aureus displayed a significantly increased adhesion to cultured osteoblasts, but its invasiveness did not differ from that of untreated controls.ConclusionOur findings demonstrate that several antibiotics at sub-MICs modulate fibronectin binding in S. aureus in a drug-specific fashion. However, hyper- and hypo- adhesive phenotypes observed in controlled in vitro conditions were not fully confirmed in whole cell infection assays. The relevance of adhesion modulation during in vivo infections is thus still uncertain and requires further investigations.

Pharmacokinetics/Pharmacodynamics of Peptide Deformylase Inhibitor GSK1322322 against Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus in Rodent Models of Infection

“…This could explain the lack of a linear relationship between the drug exposure required for efficacy and the MIC of the isolate causing the infection, particularly as repeated in vivo administration of the compound (as done in these studies) would result in exertion of this effect at regular intervals. It has already been reported for S. aureus that subinhibitory concentrations of certain antimicrobials can suppress virulence factor production (30), including production of alpha-toxin (31,32), increase susceptibility to phagocytosis (31), and modulate adherence to fibronectin (33,34). Given that antibacterial agents are often present at subinhibitory concentrations during the normal course of antibiotic therapy, these types of effects should perhaps be taken into account when evaluating the magnitude of the PK/PD indices against certain organisms.…”

Workshop report: The 2012 Antimicrobial Agents in Veterinary Medicine: exploring the consequences of antimicrobial drug use: a 3‐D approach

“…Additional references of that may be of interest include Rasigade et al ., ; Davies et al ., ; Christensen et al ., ; and Reeks et al .,.…”

“…Additional references of that may be of interest include Rasigade et al, 2011;Davies et al, 2006;Christensen et al, 2011;and Reeks et al,2005. Part 3: Emergence, transmission, and persistence of antimicrobial resistance Mechanisms of resistance and resistance transfer. Numerous mechanisms for antimicrobial resistance have been identified, and the impact of these mechanisms appears to be both drugand pathogen-specific (Table 2).…”

Potent Sub-MIC Effect of GSK1322322 and Other Peptide Deformylase Inhibitors on In Vitro Growth of Staphylococcus aureus

“…Not taken into account is any effect that the antibiotic may have at subinhibitory concentrations, a situation frequently encountered during the normal course of antibiotic therapy. Specifically in S. aureus, it has already been reported that subinhibitory concentrations of certain antibiotics can inhibit exoprotein production (28), including critical virulence factors, such as alpha-toxin (29,30), increase susceptibility to phagocytosis (29), and modulate adherence to fibronectin (31,32) and can even inhibit biofilm formation (33,34). These effects may be important in the successful treatment of S. aureus infections and should perhaps be taken into consideration in the selection of therapy (30).…”