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, AI-2, have been reported. The biological basis of antagonism, as well as the targets for these select few AI-2 antagonists, have not been clearly defined. We have developed C-1 alkyl analogs of AI-2 that quench the QS response in multiple bacterial species simultaneously. We also 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 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-AI-2 QS activities. Our results suggest entirely new modalities for interrupting or tailoring the network of communication among bacteria.
Biological nanofactories, which are engineered to contain modules that can target, sense and synthesize molecules, can trigger communication between different bacterial populations. These communications influence biofilm formation, virulence, bioluminescence and many other bacterial functions in a process called quorum sensing. Here, we show the assembly of a nanofactory that can trigger a bacterial quorum sensing response in the absence of native quorum molecules. The nanofactory comprises an antibody (for targeting) and a fusion protein that produces quorum molecules when bound to the targeted bacterium. Our nanofactory selectively targets the appropriate bacteria and triggers a quorum sensing response when added to two populations of bacteria. The nanofactories also trigger communication between two bacterial populations that are otherwise non-communicating. We envision the use of these nanofactories in generating new antimicrobial treatments that target the communication networks of bacteria rather than their viability.
Bacterial quorum sensing (QS) is a cell-cell communication process, mediated by signaling molecules, that alters various phenotypes including pathogenicity. Methods to interrupt these communication networks are being pursued as next generation antimicrobials. We present a technique for interrupting communication among bacteria that exploits their native and highly specific machinery for processing the signaling molecules themselves. Specifically, our approach is to bring native intracellular signal processing mechanisms to the extracellular surroundings and "quench" crosstalk among a variety of strains. In this study, the QS system based on the interspecies signaling molecule autoinducer-2 (AI-2) is targeted because of its prevalence among prokaryotes (it functions in over 80 bacterial species). We demonstrate that the Escherichia coli AI-2 kinase, LsrK, can phosphorylate AI-2 in vitro, and when LsrK-treated AI-2 is added ex vivo to E. coli populations, the native QS response is significantly reduced. Further, LsrK-mediated degradation of AI-2 attenuates the QS response among Salmonella typhimurium and Vibrio harveyi even though the AI-2 signal transduction mechanisms and the phenotypic responses are species-specific. Analogous results are obtained from a synthetic ecosystem where three species of bacteria (enteric and marine) are co-cultured. Finally, the addition of LsrK and ATP to growing co-cultures of E. coli and S. typhimurium exhibits significantly reduced native "cross-talk" that ordinarily exists among and between species in an ecosystem. We believe this nature-inspired enzymatic approach for quenching QS systems will spawn new methods for controlling cell phenotype and potentially open new avenues for controlling bacterial pathogenicity.
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