Inactivation of Pseudomonas aeruginosa 2-alkyl-4-hydroxyquinoline-type quorum sensing signals and antibiotics by Rhodococcus erythropolis and Mycobacterium abscessus

红平红球菌和脓肿分枝杆菌对铜绿假单胞菌 2-烷基-4-羟基喹啉型群体感应信号和抗生素的灭活

基本信息

批准号：
299367851
负责人：
Professorin Dr. Susanne Fetzner
金额：
--
依托单位：
Institut für Molekulare Mikrobiologie und Biotechnologie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2016
资助国家：
德国
起止时间：
2015-12-31 至 2019-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/299367851?language=en
关键词：
Inactivation Pseudomonas aeruginosa alkyl hydroxyquinoline

项目摘要

The opportunistic pathogen Pseudomonas aeruginosa produces a number of bioactive 2-alkyl-4(1H)-quinolones (AQ) and 2-alkyl-4-hydroxyquinoline-N-oxides. As quorum sensing signal molecules, 2-heptyl-4(1H)-quinolone (HHQ) and 2-heptyl-3-hydroxy-4(1H)-quinolone (PQS) are involved in the regulation of virulence factor production; PQS moreover has iron-chelating and membrane altering properties. 2-Heptyl-4-hydroxyquinoline-N-oxide (HQNO) has antibiotic effects, acting as inhibitor of respiratory electron transfer. We recently isolated Rhodococcus erythropolis BG43, the first bacterial strain described to specifically degrade PQS and to convert HQNO. The aqd gene cluster which in strain BG43 codes for the enzymes mediating HHQ and PQS conversion is also conserved in bacteria of the Mycobacterium abscessus complex, and we observed HQNO conversion and PQS and/or HHQ degradation by several clinical M. abscessus strains. These findings open up new perspectives for identifying enzymes involved in HQNO detoxification, for characterizing PQS-specific enzymes and assessing them as quorum quenching agents, and for studying the relevance of AQ degradation and HQNO detoxification in bacterial inter-species interactions. The genome sequences of all strains are available.The proposed project aims at: (1) Elucidating the pathway(s) of HQNO conversion: characterization of metabolites and identification of the proposed key enzyme, an N-oxide reductase. (2) Characterizing the catalytic efficiency and stability of PQS-dioxygenases of R. erythropolis BG43 and of selected M. abscessus strains, and testing the potential of the most stable and most active enzyme(s) to interfere with virulence factor production of P. aeruginosa. (3) Characterizing the potential of M. abscessus to interfere with AQ-based quorum sensing and HQNO-based antibiosis of P. aeruginosa. To this end, we will characterize the transcriptional response of the aqd gene clusters of clinical M. abscessus strains to PQS. We also will analyze the physiological response of P. aeruginosa (wild-type and pqs mutants) in co-culture with different M. abscessus strains that are able/unable to degrade PQS and/or HQNO and determine growth of M. abscessus and P. aeruginosa strains in the co-cultures.

铜绿假单胞菌的机会性病原体会产生许多生物活性2-烷基-4（1H） - 喹诺酮类（aq）和2-烷基-4-羟基羟基苯胺-N-氧化物。作为法定感应信号分子，2- heptyl-4（1H）-Quinolone（HHQ）和2-羟基-3-羟基-4（1H）-Quinolone（PQS）参与了毒力性因子产生的调节；此外，PQS具有铁螯合和膜的改变特性。 2-羟基-4-羟基喹啉-N-氧化物（HQNO）具有抗生素作用，充当呼吸电子转移的抑制剂。我们最近分离了红粒红球菌BG43，这是针对特异性降解PQ和转换HQNO的第一个细菌菌株。在BG43菌株中，AQD基因簇代码用于介导HHQ和PQS转化率的酶，也在脓肿分枝杆菌复合物的细菌中保守，我们观察到HQNO转化和PQS和/或HHQ由几个临床临床M. abscessus abscessus菌株降解。这些发现开辟了新的观点，用于鉴定与HQNO排毒有关的酶，以表征PQS特异性酶并将其评估为群体淬火剂，并研究AQ降解和HQNO排毒在细菌跨间隙相互作用中的相关性。所有菌株的基因组序列都可用。拟议的项目的目的是：（1）阐明HQNO转化率的途径：代谢物的表征和鉴定提出的键酶，N-氧化物还原酶。（2）表征了红细胞波罗氏菌BG43和选定的超麻子菌株的PQS-二加氧酶的催化效率和稳定性，并测试了最稳定和最活跃的酶（S）的潜力，以干扰铜绿假单胞菌的病毒性因子的产生。（3）表征脓肿分枝杆菌对铜绿假单胞菌的基于AQ的群体传感和基于HQNO的抗体病的潜力。为此，我们将表征临床脓肿菌株对PQ的AQD基因簇的转录响应。我们还将分析与不同的脱糖菌菌株的铜绿假单胞菌（野生型和PQS突变体）的生理反应，这些分子能够/无法降解PQS和/或HQNO，并确定脓肿菌和脓肿大麻杆菌和铜绿假单胞菌的生长。