Antimicrobial Effects Promoting Biofilm Formation and Persistent Disease: The Role of a DNA-Binding Regulator, SarA, in Staphylococcal Endocarditis

Abstract

Vancomycin, the archetypical glycopeptide introduced into clinical use as early as 1958, has been the mainstay of antiinfective therapy directed against grampositive organisms resistant to β-lactams, particularly methicillin-resistant Staphylococcusaureus(MRSA),ampicillin-resistant enterococci, and penicillin-resistant Streptococcus pneumoniae. In the early years after introduction into clinical use, numerous untoward effects were ascribed primarily to impurities (ie, the notorious “Mississippi mud,” as early preparations of vancomycin were termed, because of its impurity-tainted color), while morerecent preparations have become more acceptable because of improved manufacturing. Vancomycin’s antibacterial mode of action is well characterized and consists of an inhibition in cell wall synthesis due to tight binding of the compound to peptidoglycan monomers containing D-alanyl-D-alanine at their free carboxyl ends, resulting in steric hindrance of transglycosylase, transpeptidase, and carboxypeptidase activity and, ultimately, in cell wall synthesis interruption. As a result, the rationale for clinical use of vancomycin appears now welldefined, both with respect to mode of action and untoward side effects, yet the emergence of reduced vancomycin susceptibility remains a major clinical issue. Besides the so-called classical mode of action (target of bacterial resistance mechanisms), vancomycin exerts additional activities on bacteria, such as alteration of cell membrane permeability and inhibition of RNA synthesis [1]. Some of these effects can be ascribed to the autolysis induced by subinhibitory vancomycin concentrations affecting cell subpopulations, and leading to release of extracellular DNA [2], which, in turn, has been associated with formation and stabilization of biofilms [3].Moreover, exposure of staphylococci to subinhibitory levels of vancomycin may modify the expression of staphylococcal response regulators, such as the alternative transcription factor σ B , and of σ B -dependent