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

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.