No abstract

A screening method was established to detect inhibitors of the biosynthetic pathways of aromatic amino acids and para-aminobenzoic acid, the precursor of folic acid, using an agar A successful search for novel antibacterial metabolites has to meet three criteria, first, a specific target which is essential for the metabolism of a bacterium and not yet provided with an known inhibitor. Second, a set of taxonomically characterized and dereplicated microorganisms as producers of secondary metabolites, and last but not least a lucky but experienced hand for strain isolation and cultivation. We have chosen the shikimate pathway as an essential target of bacterial metabolism, with special consideration of the biosynthesis of aromatic amino acids and para-aminobenzoic (pAba) acid derived from the keymetabolite chorismate. Only a few antimetabolites are known as inhibitors of aromatic amino acids, such as L-2,5-dihydrophenylalanine2), an antagonist of phenlyalanine, and glyphosate that inhibits 3-enolpyruvylshikimate-3-phosphate synthase3,4). To our knowledge, no natural product inhibitor of pAba biosynthesis has been described in the literature. This pathway, which is catalyzed by two enzymes, 4-amino-4-deoxychorismic acid (ADC) synthase and ADC lyase, seems to be of considerable interest for the development of novel antibiotics since it is directly linked to folic acid biosynthesis, which is established in plants, fungi, prokaryotes and parasites of the apicomplexa group (Plasmodium, Toxoplasma) but not in vertebrates.As suitable producers of bioactive metabolites we screened within the order Actinomycetales terrestrial and marine members of the families Streptomycetaceae and Micromonosporaceae and rare actinomycete genera. A total of 930 extracts derived from 201 actinomycetes were subjected to the screening. Among them, only AB-18-032, an extract from a marine isolate from a sediment collected from the Sea of Japan, was found to exhibit activity against

Plumbing the depths: Abyssomicin C (structure shown) from ocean floor sediment is a novel antibiotic that inhibits the biosynthesis steps between chorismate and p‐aminobenzoic acid. Its activity may be explained by the irreversible trapping of the targeted enzymes by a Michael addition. Blocking the biosynthesis of p‐aminobenzoic acid may be one approach to developing new antibiotics.

Aus der Tiefe: Der Biosyntheseweg von p‐Aminobenzoesäure bietet mehrere Angriffspunkte zur Bekämpfung pathogener Mikroorganismen. Abyssomicin C (siehe Formel) ist ein neues Antibiotikum, das die Biosyntheseschritte zwischen Chorisminsäure und p‐Aminobenzoesäure hemmt. Die antibiotische Aktivität beruht möglicherweise auf einer irreversiblen Enzyminaktivierung, die durch eine Michael‐Addition vermittelt wird.

Abyssomicin C:A Polycyclic Antibiotic from a Marine Verrucosispora Strain as an Inhibitor of the p-Aminobenzoic Acid/Tetrahydrofolate Biosynthesis Pathway. -The structure of the new polycyclic polyketide-type antibiotic abyssomicin (I) is elucidated. -(BISTER, B.; BISCHOFF, D.; STROEBELE, M.; RIEDLINGER, J.; REICKE, A.; WOLTER, F.; BULL, A. T.; ZAEHNER, H.; FIEDLER, H.-P.; SUESSMUTH*, R. D.; Angew.