Synthesis
of azetidine-derived natural products by the opportunistic
pathogen Pseudomonas aeruginosa is
controlled by quorum sensing, a process involving the production and
sensing of diffusible signal molecules that is decisive for virulence
regulation. In this study, we engineered P. aeruginosa for the titratable expression of the biosynthetic aze gene cluster, which allowed the purification and identification
of two new products, azetidomonamide C and diazetidomonapyridone.
Diazetidomonapyridone was shown to have a highly unusual structure
with two azetidine rings and an open-chain diimide moiety. Expression
of aze genes strongly increased biofilm formation
and production of phenazine and alkyl quinolone virulence factors.
Further physiological studies revealed that all effects were mainly
mediated by azetidomonamide A and diazetidomonapyridone, whereas azetidomonamides
B and C had little or no phenotypic impact. The P450 monooxygenase
AzeF which catalyzes a challenging, stereoselective hydroxylation
of the azetidine ring converting azetidomonamide C into azetidomonamide
A is therefore crucial for biological activity. Based on our findings,
we propose this group of metabolites to constitute a new class of
diffusible regulatory molecules with community-related effects in P. aeruginosa.
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