# Biology and Regulation of Staphylococcusococcal Biofilm
## 2 Molecular Control of _S. aureus_ Biofilm Development and the Role of _ica_
Taken together, the expression of _ica_ plays a major role in biofilm formation but is not essential in the colonization of a surface. Interestingly [PERSON] et al. [70] showed that the expression of _ica_ is at least partially controlled by the stress response transcription factor, \(\alpha^{\text{B}}\)[71]. Studies performed with _S. aureus_ have demonstrated that the regulation of _ica_ expression and the ability to form a biofilm involve regulatory elements other than \(\alpha^{\text{B}}\) and IcaR [72]. Among these additional regulatory loci, the accessory gene regulator (_agr_) and the staphylococcal accessory regulator (_sarA_) represent important partners. Note that the interaction of SarA with _agr_ results in the promotion of biofilm formation. It was also shown that a mutation of _sarA_ resulted in a reduced capacity to form a biofilm, a phenomenon which is independent of the _icaADBC_ operon but involves various regulatory pathways, including _sar_, _taR_, and sRNA [73; 74; 75]. Factors that influence staphylococcal biofilm formation have been reviewed by [PERSON] and [PERSON] [42; 76]. The range of environmental factors altering biofilm formation appears to be indicative of the highly diverse habitats in which staphylococci are able to form biofilms. For example, the presence of oleic acid induces _S. aureus_ biofilm formation. This probably results from an ionic interaction of the positively charged PIA with the negatively charged oleic acid. The effect is even more pronounced under oxygen-limited conditions [77; 78; 79], a fact consistent with the observation that anaerbiosis is an important stimulus for _ica_ expression [46; 80]. A mature biofilm reveals an architecture that ensures the provision of nutrients and oxygen to all cells in the biofilm [3]. As they grow, bacteria begin to arrange in a three-dimensional structure composed of an array of pillars and mushroom-shaped structures. These structures are connected by convoluted channels that deliver nutrients and contribute to the elimination of waste. The maturation of biofilms has been studied by imaging and transcription profiling studies [10; 44; 81]. A primary discovery that emerged from microarray experiments is that persistence within a mature biofilm requires an adaptive response that limits the deleterious effects of pH reduction associated with anaerobic metabolism [44]. The cell envelope is a very active compartment as the expression of genes that encode binding proteins, proteins involved in the synthesis of murein and glucosaminoglycan, PIA, and other enzymes involved in the cell-envelope metabolism appears to be significantly upregulated. Thus, a biofilm is a dynamic structure that evolves with environmental conditions, such as physical shear forces, and as a result of the processes that are sensed and regulated by the bacteria. Once cell clusters reach a sufficient size, groups of cells either detach (dispersal phase) or die. Thus, it is the cycle of cell growth, detachment, and regrowth that underlies the observed patterns of organized gene expression [51; 82].