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Chemical and biological modifications of glycopeptides have long been performed in order to obtain derivatives with improved antimicrobial activity or better pharmacokinetics1). Deglycosilated derivatives of several different glycopeptides were produced and used either for biosynthetic or for antimicrobial activity studies1). Deglycosilated derivatives were mainly obtained by chemical treatment or by biotransformation with yields of up to 80%1). Particularly interesting is the biotransformation process for the yields of transformation and the selectivity of the process. However, this requires a second fermentation step and a second downstream purification. Nonomuraea sp. ATCC 39727 (formerly Actinomadura sp. ATCC 39727) is the producer of the lipoglycopeptide antibiotic complex A409262,3). A40926 is the natural precursor of the semi-synthetic derivative dalbavancin, which is currently under clinical development at Biosearch Italia SpA. Dalbavancin shows superior activity against Staphylococci and Enterococci, including some VanB isolates, and has excellent pharmacokinetic characteristics4). Antibiotic A40926 possesses the typical heptapeptide structure of the D-alanyl-D-alanine binding glycopeptides and is characterized by a Nacylaminoglucuronic acid and a mannose moiety bound to the aminoacids number 4 and 7 respectively (Figure 1). Several different related molecules have been identified in the A40926 complex3,5). The two major components of the complex are named B0 (formerly B) and B1 and are characterized respectively by an iso-C12:0 and a n-C12:0 acylic moiety bound to the aminoglucuronic acid of the antibiotic (Figure 1). A40926 aglycone and pseudoaglycones were obtained by chemical hydrolysis and subsequent purification6). The A40926 demannosyl derivative showed improved activity against some classes of Staphylococci and was also used as the starting material for the synthesis of several semisynthetic A40926 derivatives6,7). It is thus of primary importance the development of a rapid and convenient process for the production of demannosyl-A40926. In the course of a screening program for Nonomuraea sp. ATCC 39727 mutants with desirable characteristics (such as high productivity), we have isolated a clone showing a noteworthy activity in an overlay antimicrobial test. This mutant was able to directly produce demannosyl-A40926 with an abundance of ca 95% with respect to the other components of the antibiotic complex. The isolation of this strain allowed demannosyl-A40926 production by a single fermentation/purification process.

Production of Demannosyl-A40926 by a Nonomuraea sp. ATCC 39727 Mutant Strain.