Novel Targets for Treatment of Pseudomonas aeruginosa Biofilms - Antibiofilm Agents: From Diagnosis to Treatment and Prevention - page 253

at a faster rate than corresponding wild-type bacteria (Alhede et al. 2009 ; van
Gennip et al. 2009 ). Further stressing the importance of rhamnolipids is the
association between the production of rhamnolipids by colonizing P. aeruginosa
isolates and the development of Ventilator Associated Pneumonia (VAP). The
authors of the study showed that VAP occurred more frequently in patients colo-
nized during the entire observation period by isolates producing high levels of
rhamnolipids (Kohler et al. 2010 ).
In addition to rhamnolipids, QS regulates a range of other virulence factors such
as proteases, elastases, and lipases (Kharazmi et al. 1984a , b ; Doring et al. 1986 ;
Kharazmi et al. 1986 , 1989 ; Kharazmi 1991 ). Attenuating bacteria by targeting the
regulation of virulence will assist the immune system and consequently facilitate
eradication (Hentzer et al. 2003b ; Bjarnsholt et al. 2005a , b ). It has been put forward
(yet not proven) that this strategy imposes a weaker selective pressure with respect
to development of resistance compared with conventional antibiotics (Hentzer
et al. 2003a ). However, even though QSIs target non-vital functions, the fitness of
the bacteria could be reduced as a consequence of lost virulence and the presence of
immune cells and thus impose selection (Defoirdt et al. 2010 ).
In addition to controlling the production of virulence factors, QS has also been
shown to control biofilm tolerance to antibiotics such as tobramycin, ciprofloxacin,
and ceftazidime. QS-deficient biofilms are more prone to killing by these antibiotics
(Bjarnsholt et al. 2005a , b ; Bjarnsholt and Givskov 2007 ) and are less tolerant to
PMNs (Jesaitis et al. 2003 ; Bjarnsholt et al. 2005a , b ) than a QS proficient biofilm.
Since a large number of virulence factors are controlled by QS, blockage will likely
result in many beneficial effects.
Numerous researchers have searched for compounds that could block the QS
system and thereby enable biofilm eradication (Bjarnsholt and Givskov 2008 ).
Several proof of concept studies have been published, but the first promising
compounds were the synthetic furanones C-30 and C-56 (Hentzer et al. 2003b ;
Wu et al. 2004 ). QSIs do not kill or detach the biofilm directly but they render the
biofilm more susceptible to antibiotics, as was the case with these furanones. In
vitro, P. aeruginosa biofilms were significantly less tolerant to 100 ʼ g/mL
tobramycin when treated with furanone C-30 (Hentzer et al. 2003b ). In addition,
in vivo studies in a pulmonary mouse model confirmed the potential of the
furanones by demonstrating that bacteria were cleared faster in furanone-treated
vs. untreated mice (Hentzer et al. 2003b ; Wu et al. 2004 ). Recently, two QSIs from
natural sources have been isolated: Iberin from horseradish and Ajoene from garlic
(Jakobsen et al. 2012a , b ).
QS deficiency leads to reduced tolerance to a variety of conventional antibiotics,
and QSI compounds that block production of the rhamnolipid shield should make
the biofilm more prone to eradication by the immune system (Bjarnsholt
et al. 2005a , b ; Rasmussen et al. 2005 ; Alhede et al. 2009 ). Consequently, prophy-
lactic administration of QSIs or administration of QSIs in combination with anti-
biotics or other antimicrobials may become a useful strategy in the treatment of
biofilm infections. Recently, an interesting paper from Christensen et al. showed a
synergistic effect of combining tobramycin with a QSI in a murine implant