In 1972, Heinz Wolf and Hans Zähner1 described the isolation and characterization of the narrow-host range antibiotic kirromycin from the actinomycete Streptomyces collinus Tü 365. Soon after its discovery, it was shown that the observed inhibitory effect of protein biosynthesis2 is caused by the binding of kirromycin to the bacterial elongation factor EF–Tu,3 a rare molecular target for antibiotics. Kirromycin binding inhibits the conformational shift that EF–Tu normally undergoes when GTP is hydrolyzed to GDP.4 This prevents dissociation of EF–Tu from the ribosomal complex and thus blocks translation. Owing to their target, ‘elongation factor EF–Tu’ kirromycin and related antibiotics such as aurodox5 or kirrothricin6 are also referred as elfamycins.

In our previous work, the kirromycin biosynthetic gene cluster was identified, isolated and analyzed.7, 8 The linear carbon skeleton of kirromycin is synthesized by a highly complex hybrid type I polyketide synthase (PKS)/non-ribosomal peptide synthetase machinery encoded by the genes kirAI–kirAVI and kirB. The hybrid PKS/non-ribosomal peptide synthetase thereby combines trans-AT PKS architecture represented in the enzymes KirAI–KirAV with cis-AT architecture in the PKS KirAVI. Extender unit selection and loading are presumably carried out by two discrete acyltransferase enzymes, KirCI and KirCII, which are encoded in the gene cluster.8 Sequence analysis of the kirromycin biosynthetic gene cluster led to the proposal that β-alanine might be a building block for the typical pyridone moiety of kirromycin. This hypothesis was confirmed by feeding studies. Isotope-labeled β-alanine was efficiently incorporated at the expected positions in the kirromycin molecule.8

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