l Mammalian immune cells can inactivate the QS molecules for many Gram-
positive bacteria.
l Low pH can also inhibit the QS response of some Gram-positive pathogens,
which may lead to an innate mechanism to minimise biofilm formation within
certain body sites.
In human medicine, it has been observed that stress hormones or inflammatory
cytokines can be detected by bacterial QS systems. This “timing mechanism”
maximises the likelihood of successful bacterial proliferation by ensuring that
bacterial growth coincides with patient vulnerability (Asad and Opal 2008 ). In
fact, it has even been suggested that components of the host plasma proteins may
exert a critical role in determining host susceptibility to bacterial infection. For
example, Peterson et al. ( 2008 ) recently demonstrated that certain mammalian
lipoproteins interfere with the conversion from tissue colonisation to host invasion
byS. aureus.Interference of this switch is achieved by antagonising theS. aureus
agr QS system that up-regulates genes required for invasive infection.
The mechanism of antagonism entails binding of the major structural protein of
these lipoproteins, apolipoprotein B, to anS. aureusautoinducing pheromone,
thereby preventing attachment of this pheromone to the bacteria and preventing
subsequent signalling through its receptor, AgrC. Apoprotein B is an integral
structural component of low-density lipoproteins and very low-density lipoproteins.
Mice that were deficient in plasma apolipoprotein B, either genetically or pharma-
cologically induced, were more susceptible to invasive agr+ (an aggregation phe-
notype)S. aureus infection but not to infection with an agr deletion mutant.
Therefore, apolipoprotein B at homeostatic levels in blood was concluded to be
an essential innate defence effector against invasiveS. aureus infection. This
finding raises the question as to whether species differences in lipoprotein compo-
sition (Maldonado et al. 2001 , 2002 ) may lead to interspecies differences in
susceptibility toS. aureusinfections. For example, dogs tend to have fewer
problems withS. aureusinfections compared to humans (Duquette and Nuttall
2004 ; Leslie 2008 ).
When considering these QS systems it is important not to exclude the potential
for antimicrobial drugs to “interfere” with QS. Data are available that demonstrate
both up- and down-regulation of protein synthesis when bacteria are exposed to
sub-MIC concentrations of drugs, and that drugs such as the macrolides serve as QS
inhibitors (Tateda et al. 2004 ).
6 New Approaches in Antimicrobial Therapy
Antimicrobial agents can exert a broad range of effects in addition to direct
bacterial killing or interruption of bacterial replication. These effects, such as
inhibition of bacterial toxin production via inhibition of microbial protein synthesis
Antimicrobial Drug Resistance 255