Biological Implications of Tetramic Acid

描述(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的弱点成为人类机会病原体的能力。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。在过去的10年里，在阐明铜绿假单胞菌致病的分子机制方面取得了重大进展，其中群体感应起着重要的作用。LASI合成的N-(3-氧代十二烷酰基)高丝氨酸内酯(3-oxo-C12-HSL)和RhlI合成的N-丁酰高丝氨酸内酯(C4-HSL)是铜绿假单胞菌的主要群体感应信号分子。[段落]最近，我们从3-氧代-C12-HSL中发现了一种新的非酶形成的产物，新的四酸产物3-(1-hydroxydecylidene)-5-(2-hydroxyethyl)pyrrolidine-2，4-二酮(C12-TA)，从我们的PNAS出版物收到的越来越多的引用中可以看出，它引起了微生物界的兴趣。可以想象，这种四酸具有过多的生物学功能：铜绿假单胞菌可能会使用C12-TA作为干扰策略，以阻止竞争细菌的入侵。此外，由于铁(III)与C12-TA的紧密和高度特异的结合，与已知的细菌铁载体类似，我们假设这种相互作用可能作为以前未知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，它也可以作为铁隔离剂，从环境中移除游离铁，从而防止竞争细菌获得必需的铁，同时也作为反馈环，让铜绿假单胞菌表达由铁饥饿Fur/PvdS转录调控因子控制的基因。值得注意的是，我们已经表明C12-TA影响白色念珠菌的形态a。总而言之，我们将提出一系列假设，并通过高度集中的实验阐明N-(3-氧代十二烷酰基)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：我们最近发现了一种来自主要铜绿假单胞菌群体感应分子的新的非酶形成产物，并随后鉴定了一些与群体感应本身无关的生物活性，为进一步研究该分子，即C12-TA提供了基础。可以想象，铜绿假单胞菌可能使用C12-TA作为一种干扰策略，以防止竞争细菌的入侵，并将其用作铁的固存和吸收试剂，这可能是一种重要的生存策略。最终，从拟议的实验中获得的数据将有助于更深入地了解铜绿假单胞菌的发病机制，并可能揭示抗击铜绿假单胞菌感染的新的治疗靶点。

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.