Biological Implications of Tetramic Acid

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DESCRIPTION (provided by applicant): 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.