Synthetic Analogs Tailor Native Al-2 Signaling Across Bacterial Species

The widespread use of antibiotics and the emergence of resistant strains call for new approaches to treat bacterial infection. Bacterial cell cell communication or "quorum sensing" (QS) is mediated by "signatures" of small molecules that represent targets for "quenching" communication and avoiding virulent phenotypes. Only a handful of small molecules that antagonize the action of the "universal" autoinducer, Al-2, have been reported. The biological basis of antagonism, as well as the targets for these select few Al-2 antagonists, have not been clearly defined. We have developed C-1 alkyl analogs of Al-2 that quench the OS response in multiple bacterial species simultaneously. We also demonstrate the biological basis for this action. Like Al-2, the analogs are activated by the bacterial kinase, LsrK, and modulate Al-2 specific gene transcription through the transcriptional regulator, LsrR. Interestingly, addition of a single carbon to the C1-alkyl chain of the analog plays a crucial role in determining the effect of the analog on the QS response. While an ethyl modified analog is an agonist, propyl becomes an antagonist of the QS circuit. In a trispecies synthetic ecosystem comprised of E. coli, S. typhimurium, and V. harveyi we discovered both cross-species and species-specific anti-Al-2 QS activities. Our results suggest entirely new modalities for interrupting or tailoring the network of communication among bacteria.