Building Better Antibacterials

Science Signaling  04 Aug 2009:
Vol. 2, Issue 82, pp. ec259
DOI: 10.1126/scisignal.282ec259

With the increasing resistance of bacteria to antibiotics, there is a growing need for alternate therapeutic strategies to treat bacterial infection. Swem et al. built upon previous work in which their group identified a synthetic compound (4606-4237) that interfered with a type of bacterial communication called quorum sensing, which has been implicated in bacterial pathogenicity. Quorum sensing can occur through two different receptor signaling pathways. LuxN-type quorum sensing occurs at the cell surface, with LuxN-type receptors binding extracellular acyl-homoserine lactones (AHLs) and signaling through a two-component histidine phosphorelay to regulate transcription. The second involves the LuxR type of proteins, which are cytoplasmic and typically stabilized by binding to AHLs, whereupon they bind DNA to promote transcription. Swem et al. report that 4606-4237, known to antagonize LuxN-type receptors, as well as two new derivatives of this compound, chlorothiolactone (CTL) and chlorolactone (CL), antagonized the activity of LuxR-type receptors from the bacteria Chromobacterium violaceum. These compounds inhibited the transcriptional activity of the LuxR-type receptor CviR. Although the solubility of CviR was increased in the presence of these antagonists (just as in the presence of AHLs), CviR bound to the antagonists but failed to bind DNA. Swem et al. found that the two new compounds, CTL and CL, also inhibited LuxN signaling in Vibrio harveyi, and the order of potency of the compounds was similar for both types of quorum sensing: CL > CTL > 4606-4237. Survival of Caenorhabditis elegans infected with C. violaceum was improved by the application of the antagonists, validating the therapeutic potential of these antagonists. Thus, this type of antagonist may provide effective lead compounds for developing drugs to combat Gram-negative bacterial infection.

L. R. Swem, D. L. Swem, C. T. O’Loughlin, R. Gatmaitan, B. Zhao, S. M. Ulrich, B. L. Bassler, A quorum-sensing antagonist targets both membrane-bound and cytoplasmic receptors and controls bacterial pathogenicity. Mol. Cell 35, 143–153 (2009).[Online Journal]