The role of aromatic metabolites in virulence and metabolic adaptation of Acinetobacter baumannii to the human host

由于抗生素耐药性的增加，条件致病菌鲍曼不动杆菌已成为全球卫生保健机构的全球性威胁。它适应人类宿主并与之相互作用的机制的许多方面仍有待确定。虽然使用各种芳香族化合物是不动杆菌属的标志，并且在不动杆菌属中已经发现并分析了许多芳香族化合物的降解途径，对A的能力知之甚少。鲍曼不动杆菌使用芳香底物的途径及其在致病性和持久性中的作用。我们将通过分析A.鲍曼不动杆菌菌株AYE。这些化合物参与植物、动物和人类的许多不同生理和病理生理机制，并被人类宿主和病原体代谢。这些化合物的降解导致影响宿主、细菌及其关系的中间产物，例如调节宿主免疫应答和干扰病原菌与宿主免疫应答。我们最近发现A.鲍曼不动杆菌AYE和ATCC 19606在这些芳香族化合物上生长，但关于所涉及的途径的知识相当不完整（色氨酸、犬尿氨酸）或几乎不可用（犬尿氨酸）。在A.鲍曼不动杆菌及其在感染和持久性中的作用也是未知的。我们将通过遗传学和分子生物学的研究来阐明色氨酸、犬尿氨酸和犬尿氨酸的降解途径及其调控。犬尿氨酸是特别有趣的，因为犬尿氨酸降解途径在细菌中是未知的。将通过全基因组基因表达谱分析以及随后的突变体研究来鉴定对犬尿氨酸降解重要的基因。删除这些途径的酶编码基因不仅有助于解开的途径，但也将阐明感染和持久性的途径的作用。后者将通过大蜡螟和肺上皮细胞培养物中的突变体研究以及血清抗性、抗生素抗性和环境应激抗性的分析来解决。我们的研究集中在一个迄今未得到重视的一类基板的A。鲍曼不动杆菌将离开传统的途径，并将确定影响感染和持久性的新功能。鲍曼不动杆菌。

The opportunistic pathogenic bacterium Acinetobacter baumannii has become a global threat to health care institutions world wide due to increasing antibiotic resistances. Still many facets of its mechanisms to adapt and interact with the human host remain to be identified. Although use of various aromatic compounds is a hallmark of the genus Acinetobacter and many pathways for the degradation of aromatic compounds have been discovered and analyzed in Acinetobacter ssp., little is known about the capability of A. baumannii to use aromatic substrates, the pathways used and their role in pathogenicity and persistence. We will fill this gap by analyzing tryptophan, kynurenine and kynurenate metabolism in A. baumannii strain AYE. These compounds are involved in many different physiological and pathophysiological mechanisms in plants, animals and humans and are metabolized by the human host and by pathogens. Degradation of these compounds leads to intermediates which affect the host, the bacterium and their relationship such as modulating host immune response and interference of pathogenic bacteria with the host immune response. We recently found that A. baumannii AYE and ATCC19606 grow on these aromatics, but knowledge about the pathways involved is rather incomplete (tryptophan, kynurenine) or almost not available (kynurenate). Regulation of these pathways in A. baumannii is also unknown as is their role in infection and persistence. We will unravel the degradation pathways for tryptophan, kynurenine and kynurenate and their regulation by genetic and molecular studies. Kynurenate is especially interesting since a kynurenate degradation pathway is unknown in bacteria. Genes important for kynurenate degradation will be identified by genome wide gene expression profiling followed by mutant studies. Deletion of genes encoding enzymes of these pathways does not only help in unravelling the pathways but also will elucidate the role of the pathways in infection and persistence. The latter will be addressed by mutant studies in Galleria mellonella and in lung epithelial cell cultures and by analyses of serum resistance, antibiotic resistance and environmental stress resistance. Our studies focusing on a hitherto underappreciated class of substrates of A. baumannii leave traditional routes and will identify new functions that affect infection and persistence of A. baumannii.