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backbone to bind to the cell surface and then insert into the membrane, causing
disruption of the permeability barrier and lysis of the cell (
Brown and Hancock,
2006
). Many bacteria can overcome susceptibility to these compounds by modi-
fying the 1 and 4' phosphates with L-Ara4N or phosphorylethanolamine (PEtN)
by the activity of ArnT and EptA respectively, following transfer of the nascent
lipid A-core to the periplasm (
Raetz et al., 2007
). The enzymes involved in these
processes in
E. coli
are activated under specific growth conditions (e.g. growth
at low pH or in the presence of cationic peptides) and are under the regulation of
the PmrAB and PhoPQ two-component systems (
Guo et al., 1997
;
Gunn, 2008
).
An additional modification involves phosphorylation of the 1-phosphate on the
lipid A backbone to make pyrophosphate and is mediated by LpxT using undeca-
prenyl pyrophosphate as a donor (
Touze et al., 2008
). This activity helps recycle
the essential lipid carrier for peptidoglycan, O antigen, group 1 K antigens, etc.,
but other cellular proteins can also fulfill this need (
El Ghachi et al., 2005
). The
activity of LpxT is inhibited in PmrA-activated cells (
Herrera et al., 2010
).
LPS activates TLR4
During infections by Gram-negative bacteria, LPS molecules elicit an innate
immune response resulting in an inflammatory response, a property that under-
lies LPS's description as 'endotoxin'. In this intended protective process, LPS
activates macrophages, as well as some non-immune cells to secrete inflamma-
tory mediators, such as cytokines. However, in certain situations, the response
becomes dysregulated, generating a cascade of effector secretion. This can
culminate in sepsis (or septic shock), involving hypotension and organ failure,
although the details of the underlying physiological processes are not fully
understood. The process begins with recognition of LPS molecules and leads
through complex signaling pathways to cytokine induction. However, the out-
come is highly dependent on the structure of lipid A, the critical determinant
of endotoxic properties. In general, hexaacyl lipid A containing C
12
or C
14
acyl
chains is a potent activator (or agonist) of the inflammatory pathways. In con-
trast, molecules lacking one or two acyl chains (e.g. lipid IV
A
), or ones affected
in phosphorylation of the diglucosamine backbone, typically have significantly
diminished potency. These molecules are considered antagonists of the signal-
ing pathway, but their status can vary depending on the macrophage source.
Unlike
E. coli
, some bacterial species exploit the precise structural require-
ments of LPS-recognition proteins and produce naturally 'non-endotoxic'
LPS (
Munford, 2008
). Differential recognition of lipid A structures has been
exploited in the development of the universal antagonist called eritoran, a tetraa-
cyl derivative, as a therapeutic strategy to block deleterious activation of signal-
ing pathways by natural agonist LPS species (reviewed in
Bryant et al., 2010
).
LPS is an example of a PAMP and its recognition is mediated by a sen-
sory complex comprising two critical and highly conserved proteins, Toll-
like receptor 4 (TLR4) and myeloid-differentiation factor 2 (MD2) (reviewed
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