Quorum-sensing antagonists that function by stabilizing closed receptor conformations. Image: Brookhaven National Laboratory |
Among the complex molecular processes involved in the
development of bacteria-borne disease is quorum sensing, the way bacteria
communicate and coordinate collective behaviors. By studying how to inhibit
quorum sensing, scientists may be able create antibacterial pharmaceuticals for
a variety of ailments.
Recently, in part due to work performed at NSLS, researchers
from Princeton University and the Howard Hughes Medical
Institute learned how to block a quorum-sensing mechanism in the bacteria Chromobacterium
violaceum, commonly found in tropical soils and water. Although
this pathogen rarely infects humans, the group’s success indicates that their
work could lead to therapeutics for diseases caused by other bacteria types.
“The protein we studied has a close homolog in Pseudomonas aeruginosa,
a bacteria that causes particular trouble for cystic fibrosis patients,” says
the study’s lead scientist, Princeton
University molecular
biologist Frederick Hughson. “We’re hoping that the strategy we’ve discovered
might also work there.”
During quorum sensing, bacteria produce, detect, and exchange
signaling molecules known as autoinducers. This process is crucial to disease
development because it ultimately controls the way that bacteria express “virulence factors”—the molecules that enable the bacteria to colonize a host,
evade and compromise the host’s immune response, exit and enter cells, and
obtain nutrients.
Hughson and his group studied an autoinducer known as C6-HSL,
which C. violaceum detects using a
receptor of the “LuxR” family of proteins, found in the cytoplasm of many
pathogens. Without an autoinducer present, the LuxR protein, known as CviR, is
unstable and is degraded by cellular proteases. But bound to C6-HSL, CviR is
stabilized and activated. The receptor:autoinducer complex then binds to
specific sites along the cell’s DNA, “turning on” the bacterium’s virulence
genes.
In previous work, Hughson’s Princeton
colleague, Bonnie Bassler, identified a molecule that strongly inhibits quorum
sensing by binding to CviR in place of the autoinducer, thus “antagonizing” the
process. Quorum-sensing antagonists represent potential lead molecules in the
search for new antibacterial therapeutics. Especially intriguing is the
possibility that bacteria would be less likely to develop resistance to an
anti-quorum-sensing drug, because, rather than killing bacteria, it simply
keeps them from behaving badly (i.e., expressing virulence genes).
The researchers used X-rays at NSLS to “see,” for the first
time, the molecular structure of a quorum-sensing receptor bound to an
antagonist of their target. The resulting X-ray crystal structures showed that
the antagonists function by stabilizing an inactive conformation of the
receptor protein. This information should be valuable in designing
second-generation quorum-sensing antagonists with improved functional
properties.
This work was published in an online edition of Molecular Cell.
