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

• Applicant: Professorin Dr. Beate Averhoff
• Subject Area: Metabolism, Biochemistry and Genetics of Microorganisms
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 516760439

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.

• DFG Programme: Research Grants