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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.

机会致病菌铜绿假单胞菌产生许多具有生物活性的2-烷基-4（1H）-喹诺酮（AQ）和2-烷基-4-羟基喹啉-N-氧化物。2-庚基-4（1H）-喹诺酮（2-heptyl-4（1H）-quinolone，HHQ）和2-庚基-3-羟基-4（1H）-喹诺酮（2-heptyl-3-hydroxy-4（1H）-quinolone，PQS）作为群体感应信号分子，参与毒力因子产生的调控，PQS还具有铁螯合和膜改变特性。2-庚基-4-羟基喹啉-N-氧化物（HQNO）具有抗生素作用，作为呼吸电子传递的抑制剂。我们最近分离出红串红球菌BG 43，第一个细菌菌株，专门降解PQS和转化HQNO。菌株BG43中编码介导HHQ和PQS转化的酶的aqd基因簇在分枝杆菌复合体的细菌中也是保守的，并且我们观察到几种临床分枝杆菌的HQNO转化和PQS和/或HHQ降解。刺孢菌菌株。这些发现为识别参与HQNO解毒的酶、表征PQS特异性酶并评估它们作为群体猝灭剂以及研究细菌种间相互作用中AQ降解和HQNO解毒的相关性开辟了新的视角。本项目的主要目标是：（1）阐明HQNO转化途径：代谢产物的表征和关键酶N-氧化还原酶的鉴定。(2)研究了R. erythropolis BG43和M.铜绿假单胞菌菌株，并测试最稳定和最具活性的酶干扰铜绿假单胞菌毒力因子产生的潜力。(3)描述了M.干扰铜绿假单胞菌的基于AQ-based群体感应和基于HQNO的聚集。为此，我们将描述临床M的aqd基因簇的转录反应。PQS中的菌株。我们还将分析铜绿假单胞菌（野生型和pqs突变体）在与不同M.能够/不能降解PQS和/或HQNO并决定M.共培养物中的铜绿假单胞菌和铜绿假单胞菌菌株。