Isomerization of P-DPD by LsrG
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reduced activity for the N25A mutant in vitro (though not in
vivo, see above). The conservation of other active site residues,
including those shown here to be essential for function, sup-
ports the prediction that the function of LsrG in the regulation
of the Lsr system is conserved in the range of species with LsrG
homologues. The lsr operon and lsrG homologues are present
in bacteria including important human pathogens such as
S. typhimurium, B. anthracis, and Y. pestis (12) and thus can
impact communications in multispecies bacterial communities
that include pathogens such as these.
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The belief in the field is that quorum sensing can be exploited
to manipulate bacterial behavior and thus lead to an alternative
to traditional antibiotics. This is mainly because therapies that
interfere with quorum sensing are predicted to create lower
selective pressure toward resistance than traditional anti-mi-
crobial treatments (44, 45). A variety of approaches are being
developed that interfere at different steps on the quorum-sens-
ing pathways. One of these strategies, referred to as quorum
quenching, involves altering or destroying the autoinducer sig-
nal (46). Most reports on quorum-quenching approaches have
employed naturally occurring enzymes that degrade species-
specific signals. Enzymes that degrade acylhomoserine lactones
(AHLs) include AHL lactonases (47), AHL acylases (48), and
paraoxonases (49). Fewer studies have investigated interference
with autoinducer peptides, but examples of quorum-sensing
inhibition in Staphylococcus aureus are reviewed in Lyon and
Novick (50). In contrast, the Lsr system and LsrG in particular
targets the interspecies signal AI-2. This is the only natural
system known so far to degrade AI-2 signal, and there are
already multiple studies showing that the Lsr system can func-
tion as an AI-2 quenching system (11, 43). Our work shows that
interference with LsrG alters the function of Lsr, suggesting
that it could be a useful target for AI-2-based quorum-quench-
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can be particularly important when treating infections caused
by multispecies biofilms that might rely on interspecies signals
for persistence. For these cases, we predict that targeting inter-
species signaling is likely to be more effective than targeting
species-specific signals.
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Acknowledgments—We thank Frederick M. Hughson (Princeton Uni-
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Biolo´gica) for critically reading the manuscript. We thank Ana R.
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conditions and preparing the anaerobic samples, respectively. The
NMR spectrometers are part of The National NMR Network (REDE/
1517/RMN/2005), supported by “Programa Operacional Cieˆncia e
Inovac¸a˜o (POCTI) 2010” and Fundac¸a˜o para a Cieˆncia e Tecnologia.
We acknowledge National BioResource Project (Japan):E. coli for pro-
viding strain JCM62.
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18342 JOURNAL OF BIOLOGICAL CHEMISTRY
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