Biosynthetic flexibility of Pseudomonas aeruginosa leads to hydroxylated 2-alkylquinolones with proinflammatory host response

Viktoriia Savchenko; Dávid Szamosvári; Yifan Bao; Marc Pignitter; Thomas Böttcher

doi:10.1038/s42004-023-00937-y

Biosynthetic flexibility of Pseudomonas aeruginosa leads to hydroxylated 2-alkylquinolones with proinflammatory host response

Commun Chem. 2023 Jul 3;6(1):138. doi: 10.1038/s42004-023-00937-y.

Authors

Viktoriia Savchenko^{1

2}, Dávid Szamosvári¹, Yifan Bao^{2

3}, Marc Pignitter³, Thomas Böttcher⁴

Affiliations

¹ Faculty of Chemistry, Institute for Biological Chemistry & Centre for Microbiology and Environmental Systems Science, Department of Microbiology and Ecosystems Science, University of Vienna, Josef-Holaubek-Platz 2 (UZA II), 1090, Vienna, Austria.
² Vienna Doctoral School in Chemistry (DoSChem), University of Vienna, Währinger Str. 42, 1090, Vienna, Austria.
³ Faculty of Chemistry, Institute for Physiological Chemistry, University of Vienna, Josef-Holaubek-Platz 2 (UZA II), 1090, Vienna, Austria.
⁴ Faculty of Chemistry, Institute for Biological Chemistry & Centre for Microbiology and Environmental Systems Science, Department of Microbiology and Ecosystems Science, University of Vienna, Josef-Holaubek-Platz 2 (UZA II), 1090, Vienna, Austria. thomas.boettcher@univie.ac.at.

Abstract

The human pathogen Pseudomonas aeruginosa produces various 4(1H)-quinolones with diverse functions. Among these, 2-nonyl-4(1H)-quinolone (NQ) and its N-oxide (NQNO) belong to the main metabolites. Their biosynthesis involves substrates from the fatty acid metabolism and we hypothesized that oxidized fatty acids could be responsible for a so far undetected class of metabolites. We developed a divergent synthesis strategy for 2'-hydroxy (2'-OH) and 2'-oxo- substituted quinolones and N-oxides and demonstrated for the first time that 2'-OH-NQ and 2'-OH-NQNO but not the corresponding 2'-oxo compounds are naturally produced by PAO1 and PA14 strains of P. aeruginosa. The main metabolite 2'-OH-NQ is produced even in concentrations comparable to NQ. Exogenous availability of β-hydroxydecanoic acid can further increase the production of 2'-OH-NQ. In contrast to NQ, 2'-OH-NQ potently induced the cytokine IL-8 in a human cell line at 100 nм, suggesting a potential role in host immune modulation.