P8: Native enzymes and synthetic analogs tailor bacterial communication across species

Native Enzymes and Synthetic Analogs Tailor Bacterial Communication Across Species

The widespread use of antibiotics and the emergence of resistant strains call for newapproaches 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. We have developed various methods that quench the QS response based on the universal autoinducer signal AI-2 in one or multiple bacterial species simultaneously. The first method exploits the bacteria’s own native and highly specific signal processing machinery, by delivering the E. coli AI-2 kinase LsrK ex vivo to phosphorylate and degrade AI-2 before it can enter the cell. In the second approach we developed a panel of C-1 alkyl analogs of AI-2. which quench the QS response in pure or mixed cultures to different extents. We demonstrate the biological basis for this action. Like AI-2, the analogs are activated by the bacterial kinase, LsrK, and modulate AI-2 specific gene transcription through transcriptional regulator, LsrR. Interestingly, our most efficacious analogs are structurally more akin to the AI-1 family of autoinducers. In a tri-species synthetic ecosystem comprised of E. coli, S. typhimurium and V. harveyi we discovered both cross-species and species-specific anti-AI-2 QS activities. Our results suggest entirely new modalities for interrupting or tailoring the network of communication among bacteria.