The emergence of resistance among Gram-positive pathogens towards glycopeptide antibiotics has stimulated the research of second-generation molecules with improved activity and expanded antimicrobial spectrum. In this paper we investigate biotransformations as a way to generate novel teicoplanin- and A40926-like molecules. A range of commercial enzymes, fungi and actinomycetes were tested on A40926 and on its semi-synthetic derivatives (MDL 63,246 and dalbavancin). Oxidation of dalbavancin to MDL 63,246 was achieved by Nonomuraea sp. ATCC 39727 and Actinomadura parvosata ATCC 53463, while Actinoplanes sp. NRRL 3884, Actinoplanes missouriensis ATCC 23342 and Actinoplanes teichomyceticus ATCC 31121 deacylated MDL 63,246, dalbavancin and A40926. It is worth noting that the actinomycetes able to catalyze the deacylation of lipoglycopeptides are themselves producers of microbiologically active glycopeptides. Structurally related antibiotics (mideplanin and teicoplanin) were not transformed. Biotransformation conditions were optimised and scaled-up for the use of Actinoplanes sp. NRRL 3884 in the production of novel deacylated derivatives.
The emergence of resistance among Gram-positive pathogens towards glycopeptide antibiotics has stimulated the research of second-generation molecules with improved activity and expanded antimicrobial spectrum. In this paper we investigate biotransformations as a way to generate novel teicoplanin- and A40926-like molecules. A range of commercial enzymes, fungi and actinomycetes were tested on A40926 and on its semi-synthetic derivatives (MDL 63,246 and dalbavancin).
Separation of hydroxy acid enantiomers was achieved by using capillary electrochromatography (CEC) employing a chiral stationary phase (CSP) based on MDL 63,246 (Hepta-Tyr), a macrocyclic antibiotic of the teicoplanin family. The chiral selector was chemically bonded to 5 num diol-modified silica particles and the CSP mixed with amino silica (3:1 w/w) was packed into a 75 num ID fused-silica capillary. The CEC experiments were carried out by using an aqueous reversed-phase mode for the enantiomeric resolution of hydroxy acid compounds.
Biosearch Italia and Versicor are developing dalbavancin, a novel semisynthetic derivative of the natural glycopeptide A-40926 for the potential treatment of Gram-positive infections. In May 2001, the compound entered phase II trials in the US [409929], [409932]. As of Janaury 2002, phase II trials in skin infections and bacteremia were ongoing [436430].
The structure of a product, isolated during the synthesis of the semisynthetic glycopeptide MDL 63,246, was elucidated on the basis of spectroscopic methods and proved to be a novel glycopeptide containing a 3-oxazolin-5-one ring between positions 36 and 38. Subjected to acid hydrolysis this compound gave the corresponding pseudo aglycone and aglycone derivatives which maintained the original oxazolinone structure. Tested for antibacterial activity, these compounds showed a moderate activity against Gram-positive and inactive against Gram-negative bacteria.
A new glycopeptide antibiotic, MDL 63,246 (Hepta-tyr), of the teicoplanin family, has been evaluated in capillary electrophoresis for the resolution of chiral compounds of pharmaceutical and environmental interest. Electrophoretic separations were carried out in a polyacrylamide-coated capillary using the partial filling-counter current mode with aqueous-organic buffers in the pH range 4-6. Experimental parameters affecting resolution, such as antibiotic concentration, buffer pH, organic modifier type and capillary temperature, were studied.
