agrvaries between differentS.aureusisolates but tends to initialize
in mid-exponential phase after the external concentration of the
AIP reaches a threshold concentration. The four-geneagrBDCA
operon encodes a classical two-component signaling system; AgrC,
a sensor kinase, auto-phosphorylates upon binding of its cognate
AIP. The phosphoryl group is transferred to AgrA, a cytosolic
transcriptional response regulator, resulting in a conformational
change that enhances the binding of AgrA to specific DNA pro-
moter elements. For example, phosphorylated AgrA binds to and
enhances expression from the divergent P2 and P3 promoters. P2
regulates expression from theagroperon while P3 regulates expres-
sion of RNAIII, a regulatory RNA known as the “effector” of
virulence factor production inS.aureus. The final two genes of
theagroperon encode the pro-peptide AgrD and the integral
membrane endopeptidase AgrB. AgrB cleaves the carboxy tail of
AgrD and also catalyzes the cyclization of AgrD via the formation
of a thiolactone bond. The mature cyclic AIP is exported from the
cell by an as-yet unknown secretion mechanism [5, 7, 8].
S.aureuscan be separated into fouragrgroups (I–IV) where
agrclassification is dependent on the primary amino acid sequence
of the cognate AIP [9]. AIPs fromagrgroups I and IV, i.e., AIP1
and AIP4, differ by just one amino acid yet maintain a high degree
of selectivity for their respective AgrC receptor. However, AIP1 can
weakly activate AgrC4 and vice versa [10]. The amino acid
sequence and therefore the structures of AIP2 and AIP3 have
diverged so that they only activate their cognate AgrC receptor
(Fig.1). Moreover, non-cognate AIPs display competitive, cross-
group antagonism, a phenomenon that has been shown in vivo to
prevent disease progression [9, 11]. Subsequently, the cross-group
inhibition phenomenon has been successfully exploited and a num-
ber of AIP mimetics that display potent cross-group antagonism
have been synthesized [10, 12, 13]. Although AIP mimetics showFig. 1Chemical structure of AIPs 1–490 Ewan J. Murray and Paul Williams