Staphylococcus aureus Biofilm Formation and Inhibition - Antibiofilm Agents: From Diagnosis to Treatment and Prevention - page 235

can cleave PIA in the biofilm matrix and rapidly degrade the established biofilm
(Donelli et al. 2007 ; Kaplan et al. 2004 ). Kaplan et al. demonstrated that concen-
trations as low as 40 ng/mL resulted in greater than a 50 % decrease in an
established S. epidermidis biomass after 9 min, and 4.8

g/mL completely
abolished biomass in 2 min. Dispersin B is not bacteriocidal, demonstrating that
the rapid effect on biofilms is a result of PIA digestion in the matrix and destabi-
lization of the structure. However, many lineages of S. aureus form
PIA-independent biofilms that do not respond to Dispersin B treatment and instead
are sensitive to DNases or proteases (Izano et al. 2008 ). To date, no endogenous
staphylococcal PIA-degrading enzymes have been identified, but it is possible that
they remain to be discovered.

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5.5 Lysostaphin

Lysostaphin is a glycylglycine endopeptidase produced by Staphylococcus
simulans , and this enzyme cleaves the pentaglycine cross-bridge of staphylococcal
peptidoglycan (Schindler and Schuhardt 1964 ). While this enzyme is known for its
ability to lyse S. aureus cells at low concentrations, it has also been found to be
effective at inhibiting both S. aureus and S. epidermidis biofilms. At a low concen-
tration, lysostaphin will kill S. aureus cells in a biofilm and disrupt the extracellular
matrix in vitro on polystyrene and polycarbonate surfaces (Wu et al. 2003 ). When
administered in combination with nafcillin, lysostaphin was able to eradicate
established S. aureus biofilms in catheters implanted into the jugular veins of
mice (Kokai-Kun et al. 2009 ). Additionally, when catheters were pretreated with
lysostaphin, the mice were completely protected from MRSA infection of the
indwelling catheters. While this is an intriguing new method of enzymatic biofilm
dispersal, the exact mechanism by which this occurs is still unknown. One possi-
bility is that there is cell wall debris in the matrix, which is targeted by lysostaphin
resulting in biofilm disruption. Alternatively, the destruction of the biofilm could be
due to rapid lysis of cells followed by matrix destabilization (Wu et al. 2003 ).
Despite our limited understanding of the lysostaphin anti-biofilm mechanism, the
success of using this enzyme to treat staphylococcal biofilm infections suggests that
it could be attractive for further development.

6 Small-Molecule Inhibitors of S. aureus Biofilms

In recent years, there have been increasing reports of naturally occurring and
synthetic small molecules that inhibit S. aureus biofilm formation (listed in Table 2 ).
In many cases for these molecules, the anti-biofilm mechanism is not known in
detail, nor has the agent been tested in animal models of infection. We will present
the highlights from a few of the better characterized examples (see Fig. 3 ).