Communication breakdown: New strategy may be valid alternative to traditional antibiotics

Certainly there is strength in numbers, but only if those numbers can effectively communicate with one another. Now, a new study finds that administration of a novel small molecule which effectively disrupts a key bacterial communication process protects an animal host from infection. The research, published by Cell Press in the July 31st issue of the journal Molecular Cell, may lead to more effective treatments for bacterial infection that won't encourage growth of treatment resistant bacteria.

Bacteria use a process called "quorum sensing" to communicate information about population density and to synchronously engage in group behaviors that promote bacterial pathogenesis. "Quorum sensing allows bacteria to collectively carry out tasks that would be unsuccessful if carried out by an individual bacterium acting alone," explains senior study author Dr. Bonnie L. Bassler from the Howard Hughes Medical Institute and the Department of Molecular Biology at Princeton University.

During the process of quorum sensing, bacteria communicate via chemical signals called autoinducers. Autoinducers bind to receptors, called LuxR-type proteins, located inside the bacteria, or to receptors called LuxN proteins located in the bacterial membrane. In an earlier study, Dr. Bassler and colleagues discovered a class of small molecules that prevented a key autoinducer called acylhomoserine lactone (AHL) from binding to LuxN. Although LuxN and LuxR are not structurally similar, Dr. Bassler's team hypothesized that since both bind to AHLs, both may respond to the small molecule antagonists.

In the current study, the researchers demonstrated that the small molecule previously shown to block LuxN-type receptors is also a potent antagonist of LuxR receptors. This finding was somewhat surprising as these proteins are not evolutionarily related and exhibit vast differences in receptor localization, structure and signaling mechanisms. Importantly, the most potent antagonist protected nematode worms from quorum sensing-mediated killing by Chromobacterium violaceum, a human pathogen that frequently infects people through lacerated skin.

"Our results make a strong case and provide compelling evidence that an anti-quorum-sensing strategy is a valid alternative to traditional antibiotics and that there is merit to pursuing the clinical relevance of such strategies," offers Dr. Bassler. The work is also significant in that treatments based on disruption of quorum sensing interfere only with bacterial signaling and not growth, potentially minimizing the sometimes devastating development of bacteria that are resistant to treatment.

The researchers include Lee R. Swem, Princeton University, Princeton, NJ, Howard Hughes Medical Institute, Chevy Chase, MD; Danielle L. Swem, Princeton University, Princeton, NJ, Howard Hughes Medical Institute, Chevy Chase, MD; Colleen T. O'Loughlin, Princeton University, Princeton, NJ, Ithaca College, Ithaca, NY; Raleene Gatmaitan, Ithaca College, Ithaca, NY; Bixiao Zhao, Princeton University, Princeton, NJ, Scott M. Ulrich, Ithaca College, Ithaca, NY; and Bonnie L. Bassler, Princeton University, Princeton, NJ, Howard Hughes Medical Institute, Chevy Chase, MD.

July 30, 2009