Novel Targets for Treatment of Pseudomonas aeruginosa Biofilms - Antibiofilm Agents: From Diagnosis to Treatment and Prevention - page 252

3.1 Weakening of Biofilm
Most pathogenic bacteria including P. aeruginosa produce compounds that impair
the immune system, e.g., inhibition of antimicrobial production, antimicrobial
degradation, inhibition of chemotaxis, and induction of apoptosis and necrosis
(Kharazmi et al. 1984a ; Bortolussi et al. 1987 ; Kharazmi 1991 ; Allen et al. 2005 ;
Bjarnsholt et al. 2005a , b ; Jensen et al. 2007 ; Alhede et al. 2009 ). Once a chronic
infection has been established, the most obvious alternative to antibiotic-mediated
killing would be to attenuate the bacteria with respect to pathogenicity in order to
enable the immune system to clear the biofilm infection (Bjarnsholt and Givskov
2007 ). The novel treatment strategies explained in the following sections all target
the biofilm in such a way that it becomes susceptible to antibiotic treatment or the
immune system.
4 Quorum Sensing Inhibitors
Probably, the most studied novel strategy in antimicrobials is the development of
quorum sensing inhibitors (QSIs). This strategy targets the regulation of virulence
expression since bacteria, including P. aeruginosa , regulate a range of social
behaviors (e.g., metabolism, virulence, and motility) to exploit their survival
potential. Cooperative behaviors are maintained through inter- and extracellular
chemical crosstalk comparable to higher organisms (Shapiro 1998 ). Gram-negative
bacteria execute their cross talk by means of signal molecules such as N -acyl
homoserine lactones (AHLs) (Withers et al. 2001 ). Among those synchronized
activities is the expression of virulence factors (Davies et al. 1998 ; Smith and
Iglewski 2003 ). This type of bacterial communication was termed QS by (Fuqua
et al. 1994 ). QS systems allow bacteria to “sense” bacterial density in the environ-
ment and respond by gross changes in gene expression. It has been proposed that
this mechanism enables arrest in the production of virulence factors until enough
bacteria have been amassed to defeat the host defense (Waters and Bassler 2005 ).
One of the most important virulence factors produced by the model organism
P. aeruginosa is rhamnolipid. Jensen and colleagues found that P. aeruginosa
produces the compound in a QS regulated manner and proved that the bacterium
kills PMNs with this substance in liquid culture and biofilms (Jensen et al. 2007 ).
Later, Alhede et al. demonstrated that P. aeruginosa biofilms growing in vitro in
flow cells initiate rhamnolipid production upon contact with human neutrophils
(PMNs). Hence, the bacterium is able to detect the presence of these immune cells
and react by producing rhamnolipid in a QS-dependent manner. Due to the mole-
cules bipolar structure, the rhamnolipids were found to stick to the biofilm surface
and thus create a shield that kills immune cells (Alhede et al. 2009 ). The effect of
rhamnolipids in vivo has been shown in several studies and clearly demonstrates
how potent this compound is. Mutants not able to produce rhamnolipids are cleared