| Summary: | Staphylococcus epidermidis biofilm formation is a primary cause of medical device infections, which are persistent and difficult to eradicate because biofilms intrinsically exhibit a naturally high level of antibiotic resistance. Although biofilm antibiotic resistance or tolerance is a multifactorial process, some mechanisms such as limited diffusion, low metabolic activity and persister cells, contribute to the failure of antibiotics in the treatment of biofilm infections. Current, antibiotic treatment strategies may provide biofilm infections with intermittent exposure to sub-minimum inhibitory concentrations (sub-MIC) of antibiotics. Biofilms have been shown to display an increase in antibiotic tolerance when exposed to antibiotics at sub-MIC. Such mechanisms of adaptive antibiotic resistance are not well characterized but are of extreme clinical importance. This project showed that exposure to sub-MIC vancomycin increases the virulence of S. epidermidis biofilms because it induces vancomycin tolerance. BODIPY FL-vancomycin (fluorescent vancomycin conjugate) and confocal microscopy were used to show that the penetration of vancomycin through sub-MIC vancomycin pre-treated S. epidermidis biofilms was impeded, when compared to control, untreated biofilms. In addition, the results showed that a wide range of sub-MIC vancomycin concentrations induced an increased amount of extracellular DNA (eDNA) within the matrix of sub-MIC vancomycin treated biofilms. Finally, a set of ex vivo experiments using extracted exogenous S. epidermidis DNA revealed that exogenous S. epidermidis DNA binds vancomycin. Collectively these findings suggest that sub-MIC vancomycin exposure increase the abundance of eDNA in the matrix of S. epidermidis biofilms, which protects the biofilm community from subsequent vancomycin exposure by binding vancomycin as it travels through the matrix. Therefore the work in this project provides details of an eDNA-based mechanism of adaptive antibiotic tolerance in sub-MIC vancomycin treated S. epidermidis biofilms, which might be an important factor in the persistence of biofilms infections.
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