Staphylococcus aureus Biofilm Formation and Inhibition - Antibiofilm Agents: From Diagnosis to Treatment and Prevention - page 231

structural support for the biofilm and may be involved in cell-to-cell or cell-to-
surface adhesion. -toxin is the only protein identified in the S. aureus biofilm

matrix that can hold onto eDNA and provide bridging support (Huseby et al. 2010 ).
β

β

-toxin has a three-dimensional structure that resembles Nuc (Huseby et al. 2007 ),
and it is capable of binding eDNA and oligomerizing to form higher ordered states.
The multimer is protease susceptible, providing the first link between eDNA and
proteins in forming the biofilm framework, and S. aureus mutants in

β

-toxin are
defective in biofilm formation in vitro and in vivo (Huseby et al. 2010 ). However,
many clinical strains of S. aureus do not produce β -toxin due to the presence of a
converting prophage (van Wamel et al. 2006 ), suggesting that other eDNA-binding
proteins await identification in the biofilm matrix.

4 Quorum Sensing in S. aureus Biofilms

In S. aureus , biofilm formation and detachment are regulated by the agr ( a ccessory
g ene r egulator) quorum-sensing system (see Fig. 2 ). Quorum sensing is a common
mechanism utilized by most bacteria to respond to their environment and coordi-
nate a group response. In S. aureus , this self-population monitoring leads to global
changes in gene expression that influence biofilm formation, and the signal that
controls these events is an autoinducing peptide (AIP). The agr quorum-sensing
system is a chromosomal locus that encodes the proteins that produce and respond
to the AIP signal (reviewed in Thoendel et al. 2011 ; Novick and Geisinger 2008 ).
Under low agr expression conditions, cell surface protein expression is high while
secreted enzyme expression is low, making S. aureus cells more adherent and
sessile. When a critical threshold of AIP is reached, either due to growth of the
cellular community or the accumulation of a high local signal concentration, a
regulatory change occurs that leads to increased expression of the RNAIII tran-
script. RNAIII is a 514-bp transcript that is major agr effector, and high levels of
this transcript induce production of extracellular virulence factors that include
toxins, superantigens, and exo-enzymes. Multiple studies have linked the induction
of the agr system with the inhibition of S. aureus biofilms (Yarwood et al. 2004 ;
Boles and Horswill 2008 ; Lauderdale et al. 2010 ; Periasamy et al. 2012 ), and
currently the primary inhibitory factors are thought to be exo-enzymes and
phenol-soluble modulins (PSMs). These studies have demonstrated that there is
an inverse correlation between agr expression and levels of biofilm biomass,
resulting in the characteristic waves of biofilm growth and detachment seen
throughout S. aureus biofilm development (Yarwood et al. 2004 ).
The PSMs are surfactant molecules that have been identified in both S. aureus
and S. epidermidis and are under direct control by the response regulator AgrA,
which induces their transcription (Wang et al. 2007 ; Vuong et al. 2004a ; Queck
et al. 2008 ). In S. aureus , genetic deletion of the psmα operons results in

increased biofilm biomass and induction of PSMs is able to detach established
biofilms (Periasamy et al. 2012 ).

and psmβ

In the related pathogen Staphylococcus