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

鲍曼不动杆菌是一种机会致病菌，由于对抗生素耐药性的增加，已成为全球卫生保健机构的全球性威胁。然而，其适应和与人类宿主互动的机制的许多方面仍有待确定。虽然利用各种芳香族化合物是不动杆菌属的标志，并且已经在不动杆菌中发现和分析了许多降解芳香族化合物的途径，但对鲍曼不动杆菌利用芳香底物的能力、所使用的途径及其在致病性和持久性中的作用知之甚少。我们将通过分析鲍曼不动杆菌AYE菌株的色氨酸、犬尿氨酸和犬尿酸代谢来填补这一空白。这些化合物参与了植物、动物和人类许多不同的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中间体的产生，从而影响宿主、细菌以及它们之间的关系，如调节宿主免疫反应、干扰病原菌对宿主免疫反应的干扰等。我们最近发现A.baumannii aye和ATCC19606生长在这些芳烃上，但关于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(犬尿酸)。鲍曼不动杆菌对这些途径的调控以及它们在感染和持久性中的作用也是未知的。我们将通过遗传和分子研究来揭示色氨酸、犬尿氨酸和犬尿酸的降解途径及其调控。Kynurenate特别有趣，因为Kynurenate在细菌中的降解途径是未知的。对犬尿酸降解至关重要的基因将通过全基因组基因表达谱进行鉴定，随后进行突变研究。这些途径的酶编码基因的缺失不仅有助于解开这些途径，而且还将阐明这些途径在感染和持久性中的作用。后者将通过对Galeria mellonella和肺上皮细胞培养的突变研究以及血清耐药性、抗生素耐药性和环境应激抗性的分析来解决。我们的研究集中在一类迄今未被认识的鲍曼不动杆菌底物，将离开传统途径，并将确定影响鲍曼不动杆菌感染和持久性的新功能。

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.