has an incredible ability to survive, either by adapting to environmental conditions or defending against exogenous stress. Although there are certainly important genetic traits, in part this ability is provided by the breadth of modes of growth can adopt. It has been proposed that while within their host, survives host-generated and therapeutic antimicrobial stress via alternative lifestyles: a persister sub-population, through biofilm growth on host tissue or by growing as small colony variants (SCVs). Key to an understanding of chronic and relapsing infections is determining the molecular basis for its switch to these quasi-dormant lifestyles. In a multicellular biofilm, the metabolically quiescent bacterial community additionally produces a highly protective extracellular polymeric substance (EPS). Furthermore, there are bacteria within a biofilm community that have an altered physiology potentially equivalent to persister cells. Recent studies have directly linked the cellular ATP production by persister cells as their key feature and the basis for their tolerance of a range of antibiotics. In clinical settings, SCVs of have been observed for many years; when cultured, these cells form non-pigmented colonies and are approximately ten times smaller than their counterparts. Various genotypic factors have been identified in attempts to characterize SCVs and different environmental stresses have been implicated as important inducers.

dAn undetermined feature of Staphylococcus aureus pathogenesis is its persistence and then relapse of disease. This has been explained by its switch to alternative lifestyles, mainly as biofilm or small-colony variants (SCVs). Studying the native characteristics of SCVs has been problematic due to their reversion to the parental lifestyle. We have observed that for a number of S. aureus strains as they switch to an SCV lifestyle, there is the formation of an extracellular matrix. We focused our analysis on one strain, WCH-SK2. For bacterial survival in the host, the combination of low nutrients and the prolonged time frame forms a stress that selects for a specific cell type from the population. In this context, we used steady-state growth conditions with low nutrients and a controlled low growth rate for a prolonged time and with methylglyoxal. These conditions induced S. aureus WCH-SK2 into a stable SCV cell type; the cells did not revert after subculturing. Analysis revealed these cells possessed a metabolic and surface profile that was different from those of previously described SCVs or biofilm cells. The extracellular matrix was protein and extracellular DNA but not polysaccharide. The SCV cells induced expression of certain surface proteins (such as Ebh) and synthesis of lantibiotics while downregulating factors that stimulate the immune response (leucocidin, capsule, and carotenoid). Our data reveal cell heterogeneity within an S. aureus population and under conditions that resemble long-term survival in the host have identified a previously unnoticed S. aureus cell type with a distinctive metabolic and molecular profile. Staphylococcus aureus has an incredible ability to survive, either by adapting to environmental conditions or defending against exogenous stress. In part, this ability is provided by the breadth of lifestyles or modes of growth S. aureus can adopt. Key to an understanding of chronic, persistent, and relapsing S. aureus infections is determining the basis for their switch to quasi-dormant lifestyles. Across different bacterial species, these alternative lifestyles form a population known as persister cells (1). It has been proposed that while within their host, a subpopulation of S. aureus survives host-generated and therapeutic antimicrobial stresses by inducing biofilm growth on host tissue or by growing as smallcolony variants (SCVs). It is likely this is not an on-off switch, from planktonically growing cells to a biofilm or likewise to SCVs, but a continuum of cell types; the bacterial population will have the potential for a diverse range of lifestyles defined by different metabolic pathways and surface structures. In a multicellular biofilm, the metabolically quiescent bacterial community produces a highly protective extracellular polymeric substance (EPS). The EPS is variously composed of polysaccharides (mainly the ica operon-encoded polysaccharide intercellular adhesin [PIA]), extracellular DNA (eDNA), and protein, and its protection results in persistent bacterial infections (...

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