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Abyssomicins: Formation of unusual polyketides

 


Coworkers: Dr. Agnes Mühlenweg, Annette Poch

Keywords: polyketides, PKS, p-aminobenzoate/folate biosynthesis inhibitor, tetronic acid

Cooperation: Prof. Hans-Peter Fiedler, University of Tübingen, Prof. Peter Leadley, Cambridge University, UK

 

 



Polyketides are a group of secondary metabolites and serve as potent antiinfectives. Abyssomicins constitute an important subgroup of polyketides, which are characterized by an oxabicyclooctane system and a tetronic acid unit. These products were identified and isolated in cooperation with the Fiedler group in Tübingen in the context of a biological screening for inhibitors of p-aminobenzoate (pABA) in Verrucosispora maris AB-18-032.

The organism produces different types of Abyssomicins based on the biosynthesis of linear polyketide precursors. The most famous example of the Abyssomicins is Abyssomicin C. We could show, that atrop-Abyssomicin C  is the main product, while Abyssomicin C occurs as a more stable but less active artifact during purification. Atrop-Abyssomicin C and Abyssomicin C are potent against a variety of Gram-positive bacteria including pathogenic and drug resistant strains like MRSA. Studies related to the mode of action revealed them as covalent inhibitors of PabB and therefore as potent inhibitors of the biosynthesis of folic acid in microorganisms. Due to this fact Abyssomicin C and derivatives seem to be very potential drug candidates to overcome the gap of new antibiotics and the growing resistance problem.

The formation of the tetronic acid unit and the evolutionary relation of biosynthetic gene clusters of different Abyssomicin producers are subject to investigations.  Currently, various Abyssomicin producing strains are investigated and compared to each other to elucidate the underlying biosynthetic mechansims. Furthermore combinatorial biosynthesis approaches could enable the generation of novel Abyssomicin derivatives.

Figure 1. Structures of Abyssomicins C (1a), B (2), D (4), G (5), H (5) and atrop-Abyssomicin C (1b).