New and Unexpected Insights into the Modulation of LuxR-Type Quorum Sensing by Cyclic Dipeptides
- 23 November 2009
- journal article
- research article
- Published by American Chemical Society (ACS) in ACS Chemical Biology
- Vol. 4 (12), 1051-1059
- https://doi.org/10.1021/cb900165y
Abstract
Quorum sensing (QS) is under the control of N-acylated l-homoserine lactones (AHLs) and their cognate receptors (LuxR-type proteins) in Gram-negative bacteria and plays a major role in mediating host–bacteria interactions by these species. Certain cyclic dipeptides (2,5-diketopiperazines, DKPs) have been isolated from bacteria and reported to activate or inhibit LuxR-type proteins in AHL biosensor strains, albeit at significantly higher concentrations than native lactones. These reports have prompted the proposal that DKPs represent a new class of QS signals and potentially even interspecies or interkingdom signals; their mechanisms of action and physiological relevance, however, remain unknown. Here, we describe a library of synthetic DKPs that was designed to (1) determine the structural features necessary for LuxR-type protein activation and inhibition and (2) probe their mechanisms of action. These DKPs, along with several previously reported natural DKPs, were screened in bacterial reporter gene assays. In contrast to previous reports, the native DKPs failed to exhibit either antagonistic or agonistic activities in these assays. However, non-natural halogenated cyclo(l-Pro-l-Phe) derivatives were capable of inhibiting luminescence in Vibrio fischeri. Interestingly, additional experiments revealed that these DKPs do not compete with the natural lactone signal, OHHL, to inhibit luminescence. Together, these data suggest that DKPs are not QS signals in the bacteria examined in this study. Although these compounds can influence QS-regulated outcomes, we contend that they do not do so through direct interaction with LuxR-type proteins. This work serves to refine the lexicon of naturally occurring QS signals used by Gram-negative bacteria.Keywords
This publication has 48 references indexed in Scilit:
- Microfluidic Confinement of Single Cells of Bacteria in Small Volumes Initiates High‐Density Behavior of Quorum Sensing and Growth and Reveals Its VariabilityAngewandte Chemie-International Edition, 2009
- Evaluation of a focused library of N-aryl l-homoserine lactones reveals a new set of potent quorum sensing modulatorsBioorganic & Medicinal Chemistry Letters, 2008
- Expanding dialogues: from natural autoinducers to non-natural analogues that modulate quorum sensing in Gram-negative bacteriaChemical Society Reviews, 2008
- Comparative Analyses of N‐Acylated Homoserine Lactones Reveal Unique Structural Features that Dictate Their Ability to Activate or Inhibit Quorum SensingChemBioChem, 2008
- Modulation of Bacterial Quorum Sensing with Synthetic Ligands: Systematic Evaluation of N-Acylated Homoserine Lactones in Multiple Species and New Insights into Their Mechanisms of ActionJournal of the American Chemical Society, 2007
- Two-Component Response Regulators ofVibrio fischeri: Identification, Mutagenesis, and CharacterizationJournal of Bacteriology, 2007
- N-Phenylacetanoyl-l-Homoserine Lactones Can Strongly Antagonize or Superagonize Quorum Sensing in Vibrio fischeriACS Chemical Biology, 2007
- Novel Pseudomonas aeruginosa Quorum-Sensing Inhibitors Identified in an Ultra-High-Throughput ScreenAntimicrobial Agents and Chemotherapy, 2006
- Listening in on bacteria: acyl-homoserine lactone signallingNature Reviews Molecular Cell Biology, 2002
- Quorum-sensing in Gram-negative bacteriaFEMS Microbiology Reviews, 2001