Pseudomonas aeruginosa is a common environmental microorganism that has acquired the ability to take advantage of weaknesses in the host immune system to become an opportunistic pathogen in humans. Most prominent is the role of P. aeruginosa in patients suffering from cystic fibrosis as lung defense functions are severely impaired. Over the last 10 years, significant progress has been made in elucidating the molecular mechanisms underlying P. aeruginosa pathogenicity, in which quorum sensing plays a significant role. Two different AHLs, N-(3-oxododecanoyl) homoserine lactone (3-oxo- C12-HSL), synthesized by LasI, and N-butyrylhomoserine lactone (C4-HSL), synthesized by RhlI, have been identified as the main quorum sensing signaling molecules in P. aeruginosa. [PARAGRAPH] Recently, our discovery of a new nonenzymatically-formed product from 3-oxo-C12-HSL, the novel tetramic acid product, 3-(1-hydroxydecylidene)-5-(2-hydroxyethyl)pyrrolidine- 2,4-dione (C12-TA), has generated interest in the microbiological community as evident by the increasing number of citations our PNAS publication has received. Conceivably, this tetramic acid has a plethora of biological functions: P. aeruginosa might use C12-TA as an interference strategy to preclude encroachment by competing bacteria. Additionally, due to the tight and highly specific binding of iron(III) to C12-TA, comparable to known bacterial siderophores, we have hypothesized that this interaction may serve as a previously unrecognized primordial mechanism for iron solubilization and may provide P. aeruginosa with a competitive advantage in complex bacterial communities. Alternatively it might serve as an iron sequestering agent, removing free iron from the environment, thus preventing competing bacteria from obtaining essential iron while also serving as a feedback loop for P. aeruginosa to express genes controlled by the iron starvation Fur/PvdS transcription regulators. Significantly, we have shown that C12-TA affects morphology a in Candida albicans. [PARAGRAPH] Taken in total, we will present a set of hypotheses with highly focused experiments elucidate the molecular features and biochemical functions of N-(3-oxododecanoyl) homoserine lactone-derived C12-TA.

Public Health Relevance

Our recent discovery of a new nonenzymatically-formed product derived from the main Pseudomonas aeruginosa quorum sensing molecule and the subsequent identification of a number of biological activities unrelated to quorum sensing itself provides the basis for further biochemical studies of this molecule, namely C12-TA. It is conceivable that P. aeruginosa might use C12-TA as an interference strategy to preclude encroachment by competing bacteria as well utilization as an iron sequestration and uptake agent, which might be an important survival strategy. Ultimately, the data obtained from the proposed experiments will lead to a deeper understanding of the P. aeruginosa pathogenesis and may uncover new therapeutic targets for combating P. aeruginosa infections.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Exploratory/Developmental Grants (R21)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-IDM-A (90))
Program Officer
Taylor, Christopher E,
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Scripps Research Institute
La Jolla
United States
Zip Code
Garner, Amanda L; Yu, Jing; Struss, Anjali K et al. (2013) Immunomodulation and the quorum sensing molecule 3-oxo-C12-homoserine lactone: the importance of chemical scaffolding for probe development. Chem Commun (Camb) 49:1515-7
Struss, Anjali K; Nunes, Ashlee; Waalen, Jill et al. (2013) Toward implementation of quorum sensing autoinducers as biomarkers for infectious disease states. Anal Chem 85:3355-62
Garner, Amanda L; Kim, Sook Kyung; Zhu, Jie et al. (2012) Stereochemical insignificance discovered in Acinetobacter baumannii quorum sensing. PLoS One 7:e37102
Lowery, Colin A; Kaufmann, Gunnar F; Janda, Kim D (2011) Determination of acyl homoserine lactone and tetramic acid concentrations in biological samples. Methods Mol Biol 692:101-11
Garner, Amanda L; Yu, Jing; Struss, Anjali Kumari et al. (2011) Synthesis of 'clickable' acylhomoserine lactone quorum sensing probes: unanticipated effects on mammalian cell activation. Bioorg Med Chem Lett 21:2702-5
Lowery, Colin A; Salzameda, Nicholas T; Sawada, Daisuke et al. (2010) Medicinal chemistry as a conduit for the modulation of quorum sensing. J Med Chem 53:7467-89
Lowery, Colin A; Park, Junguk; Gloeckner, Christian et al. (2009) Defining the mode of action of tetramic acid antibacterials derived from Pseudomonas aeruginosa quorum sensing signals. J Am Chem Soc 131:14473-9
Lowery, Colin A; Abe, Takumi; Park, Junguk et al. (2009) Revisiting AI-2 quorum sensing inhibitors: direct comparison of alkyl-DPD analogues and a natural product fimbrolide. J Am Chem Soc 131:15584-5