Elucidation of the biosynthesis of 4-hydroxy-2-alkylquinolines by pseudomonas aeruginosa

近年来，已经证明细菌在一个被称为“群体感应”的过程中相互交流。在这种机制中，细菌分泌一种或多种信号分子，当它们在培养基中达到特定浓度时，与相应的调节蛋白结合，从而增加信号化合物的产生，并激活其他毒力基因。在感染的早期阶段，这种同步行为的好处是等待，直到细菌数量足够大，这样同时释放的毒力因子可以压倒宿主的防御。在这项研究中，我们想要表征一个新的信号分子家族- 4-羟基-2-烷基喹啉（HAQs）的生物合成所涉及的酶系统。这些化合物是铜绿假单胞菌（Pseudomonas aeruginosa）产生的信号分子，这是一种导致囊性纤维化患者死亡的机会性病原体。这项工作的目的是分离负责HAQ合成的酶，以便更好地了解它们的功能，并最终找到这些酶的特异性抑制剂。通过阻止这些化合物的合成，我们相信我们可以抑制该细菌的部分群体感应机制，从而降低其致病性。抑制细菌的毒力是另一种预防感染的方法，将消灭毒性较弱的细菌的作用留给宿主的自然防御。这种方法可能不太容易产生耐药性，这是一个困扰抗生素使用的问题，这些抗生素针对的是细菌的生存能力而不是毒性。

In recent years it has been demonstrated that bacteria communicate with one another, in a process called « Quorum Sensing ». In this mechanism, bacteria secrete one or many signalling molecules which, when they have reched a specific concentration in the medium, bind to their corresponding regulator protein that will increase the production of the signalling compounds and will also activate other virulence genes. During the early stage of an infection, the advantage of such synchronized behaviour is to wait until the number of bacteria is sufficiently large so that the simultaneous release of virulence factor could overwhelm the host defence.In this study, we want to characterize the enzymatic systems involved in the biosynthesis of one new family of signalling molecules called 4-hydroxy-2-alkylquinolines (HAQs). These compounds are signalling molecules produced by Pseudomonas aeruginosa , an opportunistic pathogen responsible for most fatalities for people afflicted with cystic fibrosis. The objective of the work is to isolate the enzymes responsible for HAQ synthesis in order to better understand how they function and eventually find specific inhibitors of these enzymes. By preventing the synthesis of these compounds, we believe we could inhibit part of the quorum sensing mechanism in this bacterium, and thus reduce its pathogenicity. Inhibiting bacterial virulence is another way to prevent an infection, leaving to the host natural defence the role of eliminating a bacteria rendered less virulent. This approach is likely to be less prone to the development of resistance, a problem that pleagues the use of antibiotics which target bacterial viability rather than virulence.