Biological Implications of Tetramic Acid

描述（由申请人提供）：铜绿假单胞菌是一种常见的环境微生物，它已经获得了利用宿主免疫系统弱点的能力，成为人类的机会性病原体。最突出的是铜绿假单胞菌在囊性纤维化患者中的作用，因为肺防御功能严重受损。近10年来，铜绿假单胞菌致病性的分子机制研究取得了重大进展，群体感应在其中发挥了重要作用。LasI合成的N-（3-氧十二烷基）高丝氨酸内酯（3-氧- C12-HSL）和RhlI合成的N-丁基高丝氨酸内酯（C4-HSL）是铜绿假单胞菌中主要的群体感应信号分子。【段落】最近，我们从3-氧- c12 - hsl中发现了一种新的非酶形成的产物，新型四羧酸产物，3-（1-羟基癸基）-5-（2-羟乙基）吡咯烷- 2,4-二酮（C12-TA），引起了微生物界的兴趣，我们的PNAS出版物收到的引用次数越来越多。可以想象，这种四羧酸具有过多的生物学功能：铜绿假单胞菌可能使用C12-TA作为干扰策略来阻止竞争细菌的入侵。此外，由于铁（III）与C12-TA的紧密和高度特异性结合，与已知的细菌铁载体相当，我们假设这种相互作用可能是一种以前未被认识到的铁溶解的原始机制，并可能为铜绿假单胞菌在复杂的细菌群落中提供竞争优势。或者，它可能作为一种铁隔离剂，从环境中去除游离铁，从而阻止竞争细菌获得必需的铁，同时也作为铜绿假单胞菌表达由铁饥饿Fur/PvdS转录调节因子控制的基因的反馈回路。值得注意的是，我们已经表明C12-TA影响白色念珠菌的形态。[段落]总的来说，我们将提出一系列假设，并进行高度集中的实验，阐明N-（3-氧十二烷基）高丝氨酸内酯衍生的C12-TA的分子特征和生化功能。公共卫生相关性：我们最近发现了铜绿假单胞菌主要群体感应分子的一种新的非酶形成产物，并随后鉴定了与群体感应本身无关的许多生物活性，为进一步研究该分子（即C12-TA）提供了基础。可以想象，P. aeruginosa可能利用C12-TA作为一种干扰策略来阻止竞争细菌的入侵，并利用其作为铁的固存和摄取剂，这可能是一种重要的生存策略。最终，从所提出的实验中获得的数据将导致对铜绿假单胞菌发病机制的更深入了解，并可能发现新的治疗靶点，以对抗铜绿假单胞菌感染。

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.