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1.  A Multivalent Probe for AI-2 Quorum Sensing Receptors 
Journal of the American Chemical Society  2011;133(40):15934-15937.
Multivalency is a common principle in the recognition of cellular receptors, and multivalent agonists and antagonists have played a major role in understanding mammalian cell receptor biology. The study of bacterial cell receptors using similar approaches, however, has lagged behind. Herein we describe our efforts toward the development of a dendrimer-based multivalent probe for studying AI-2 quorum sensing receptors. From these studies, we have discovered a chemical probe specific for Lsr-type AI-2 quorum sensing receptors with the potential for enabling the identification of new bacterial species that utilize AI-2 as a quorum sensing signaling molecule.
doi:10.1021/ja207556d
PMCID: PMC3203215  PMID: 21913711
2.  Synthesis of “clickable” acylhomoserine lactone quorum sensing probes: unanticipated effects on mammalian cell activation 
Alkynyl- and azido-tagged 3-oxo-C12-acylhomoserine lactone probes have been synthesized to examine their potential utility as probes for discovering the mammalian protein target of the Pseudomonas aeruginosa autoinducer, 3-oxo-C12-acylhomoserine lactone. Although such substitutions are commonly believed to be quite conservative, from these studies, we have uncovered a drastic difference in activity between the alkynyl- and azido-modified compounds, and provide an example where such structural modification has proved to be much less than conservative.
doi:10.1016/j.bmcl.2010.11.122
PMCID: PMC3081916  PMID: 21190852
Acylhomoserine lactones; Click chemistry; Pseudomonas aeruginosa; Quorum sensing
3.  Revisiting AI-2 quorum sensing inhibitors: Direct comparison of alkyl-DPD analogs and a natural product fimbrolide 
Journal of the American Chemical Society  2009;131(43):15584-15585.
Quorum sensing (QS) systems have been proposed in a wide variety of bacteria. The AI-2-based QS system represents the most studied of these proposed interspecies systems, and has been shown to regulate diverse functions such as bioluminescence, expression of virulence factors, and biofilm formation. As such, the development of modulatory compounds, both agonists and antagonists, is of great interest for the study of unknown AI-2 based QS systems and the potential treatment of bacterial infections. The fimbrolide class of natural products has exhibited excellent inhibitory activity against AI-2-based QS, and as such may be considered the “gold-standard” of AI-2 inhibitors. Thus, we sought to include a fimbrolide as a control compound for our recently developed alkyl-DPD panel of AI-2 modulators. Herein, we present a revised synthesis of a commonly studied fimbrolide, as well as a direct comparison between the fimbrolide and alkyl-DPD analogs. We demonstrate that our alkyl-DPD analogs are more potent inhibitors of QS in both Vibrio harveyi and Salmonella typhimurium, the two organisms with defined AI-2 systems, and in doing so, call into question the widely accepted use of fimbrolide-derived compounds as the “gold standard” of AI-2 inhibition.
doi:10.1021/ja9066783
PMCID: PMC2784249  PMID: 19824634
4.  Defining the Mode of Action of Tetramic Acid Antibacterials Derived from Pseudomonas aeruginosa Quorum Sensing Signals 
Journal of the American Chemical Society  2009;131(40):14473-14479.
In Nature, bacteria rarely exist as single, isolated entities, but rather as communities comprised of many other species including higher host organisms. To survive in these competitive environments, microorganisms have developed elaborate tactics such as the formation of biofilms and the production of antimicrobial toxins. Recently, it was discovered that the Gram-negative bacterium Pseudomonas aeruginosa, an opportunistic human pathogen, produces an antibiotic, 3-(1-hydroxydecylidene)-5-(2-hydroxyethyl)pyrrolidine-2,4-dione (C12-TA), derived from one of its quorum sensing molecules. Here, we present a comprehensive study of the expanded spectrum of C12-TA antibacterial activity against microbial competitors encountered by P. aeruginosa in Nature as well as significant human pathogens. The mechanism of action of C12-TA was also elucidated and C12-TA was found to dissipate both the membrane potential and pH gradient of Gram-positive bacteria, correlating well with cell death. Notably, in stark contrast to its parent molecule 3-oxo-dodecanoyl homoserine lactone (3-oxo-C12-HSL), neither activation of cellular stress pathways nor cytotoxicity was observed in human cells treated with C12-TA. Our results suggest that the QS machinery of P. aeruginosa has evolved for a dual-function, both to signal others of the same species, and also to defend against both host immunity and competing bacteria. Because of the broad-spectrum antibacterial activity, established mode of action, lack of rapid resistance development, and tolerance by human cells, the C12-TA scaffold may also serve as a new lead compound for the development of antimicrobial therapeutics.
doi:10.1021/ja9056079
PMCID: PMC2760024  PMID: 19807189
5.  The quorum quenching antibody RS2-1G9 protects macrophages from the cytotoxic effects of the Pseudomonas aeruginosa quorum sensing signalling molecule N-3-oxo-dodecanoyl-homoserine lactone 
Molecular immunology  2008;45(9):2710-2714.
The Gram-negative bacterium Pseudomonas aeruginosa, an opportunistic human pathogen, uses acylhomoserine lactone-based quorum sensing systems to control its pathogenicity. One of its quorum sensing factors, N-3-oxo-dodecanoyl homoserine lactone, has been shown not only to mediate bacterial quorum sensing but also to exert cytotoxic effects on mammalian cells. The monoclonal antibody RS2-1G9 generated against a 3-oxo-dodecanoyl homoserine lactone analogue hapten was able to protect murine bone marrow-derived macrophages from the cytotoxic effects and also prevented the activation of the mitogen-activated protein kinase p38. These data demonstrate that an immunopharmacotherapeutic approach to combat P. aeruginosa infections might be a viable therapeutic option as the monoclonal antibody RS2-1G9 can readily sequester bacterial N-3-oxo-dodecanoyl homoserine lactone molecules, thus interfering with their biological effects in prokaryotic and eukaryotic systems.
doi:10.1016/j.molimm.2008.01.010
PMCID: PMC2359578  PMID: 18304641
7.  Infection control by antibody disruption of bacterial quorum sensing signaling 
Chemistry & biology  2007;14(10):1119-1127.
Summary
Quorum sensing (QS) is the process through which bacteria communicate utilizing small diffusible molecules termed autoinducers. It has been demonstrated that QS controls a plethora of microbial processes including the expression of virulence factors. Here, we report an immunopharmacotherapeutic approach for the attenuation of QS in the Gram-positive human pathogen Staphylococcus aureus. An anti-autoinducer monoclonal antibody, AP4-24 H11, was elicited against a rationally-designed hapten, and efficiently inhibited QS in vitro through the sequestration of the autoinducing peptide (AIP)-4 produced by S. aureus RN4850. Importantly, AP4-24H11 suppressed S. aureus pathogenicity in an abscess formation mouse model in vivo and provided complete protection against a lethal S. aureus challenge. These findings provide a strong foundation for further investigations of using immunopharmacotherapy for the treatment of bacterial infections in which QS controls the expression of virulence factors.
doi:10.1016/j.chembiol.2007.08.013
PMCID: PMC2088803  PMID: 17961824

Results 1-7 (7)