Parvodicin, a novel glycopeptide from a new species, Actinomadura parvosata: Discovery, taxonomy, activity and structure elucidation.

Abstract

An extensive taxonomic investigation identified strain SK&F-AAJ-271 as a newspecies, designated Actinomadura parvosata. Fermentations of this organism produce a complex of acidic, lipophilic glycopeptide antibiotics, the parvodicins. Structures for seven of the isolated components were derived from a combination of mass spectral, high-field NMRand chemical techniques. The O-acetyl functionality present in two of the isolated components is a structural feature unique amongthe knownmembersof this class of antibiotics. The parvodicins are active in vitro against a range of Gram-positive bacteria. The most active parvodicin, Q, produces high serum levels in vivo and has the potential for a long duration of action.The increasing importance of vancomycin for the treatment of methicillin-resistant staphylococcal infections1*10 has stimulated the search for novel membersof this class of glycopeptide antibiotics. Central to our effort in this area has been a mechanism-based screen3) in which a mimetic of the bacterial cell wall receptor4) for glycopeptides is used to antagonize selectively the activity of these antibiotics in the complex mixture of culture products, the implementation of efficient isolation and purification procedures,5>6) as well as the development of fast atom bombardment mass spectrometry (FAB-MS) techniques7) and modern two-dimensional (2D) NMRmethods8) for structural characterization. This strategy has led to the discovery, isolation and structure elucidation of the aridicins,8~10) the kibdelins11'125 and as reported in detail here, the parvodicins.13) Materials and Methods Chemotaxonomy, Physiological and Biochemical EvaluationStrain SK&F-AAJ-271 was isolated from a soil sample collected on the shore of a pond or stream near Myittanyunt, Burma. Because SK&F-AAJ-271sporulates poorly, the culture was grown in shake flasks and maintained as frozen stock in a mechanical freezer at -70°C or in the vapor phase of liquid nitrogen. Slant cultures were maintained on thin inorganic salts -starch agar (Difco inorganic salts -starch agar (ISP 4) 12 g, Difco Bactoagar 15 g, distilled water (1 liter) supplemented with yeast extract (2 g/liter)). Morphological observations were made on plates of modified thin inorganic saltsstarch agar (Difco inorganic salts -starch agar (ISP 4) 12 g, Difco Bactoagar 15 g, distilled water 800 ml, soil extract 200 ml, thiamine hydrochloride 0.5 mg, biotin 0.25 mg). Color descriptions were chosen by comparison to color chips from the ISCC-NBSColor Charts14) or the Methuen Handbook of

Antibacterial activities and modes of action of vancomycin and related glycopeptides

“…Several glycopeptides containing a long-chain aliphatic acyl residue on one of the amino sugars have been reported (8,9,19,32,39). Some of these compounds were reported to be superior in antibacterial activity and pharmacokinetics to vancomycin (10).…”

Antibiotics: opportunities for genetic manipulation

“…Although streptomycetes seem to produce members of every antibiotic class also produced by other individual genera (Okami & Hotta 1988), different members of some antibiotic classes may be confined to particular organisms. In any event, the strategy of screening 'unusual' actinomycetes has had some recent successes, yielding, for example, teicoplanins from Actinoplanes (Parend et al 1977), aridicins from Kibdelosporangium (Sitrin et al 1985) and parvodicins from Actinomadura (Christensen et al 1987). (There has also been a tendency to re-classify some known antibiotic-producing members of the genus Streptomyces in 'minority' genera, such as Saccharopolyspora for the erythromycin producer and Amycolatopsis for the rifamycin producer!…”

Karamomycins A–C: 2-Naphthalen-2-yl-thiazoles from Nonomuraea endophytica

“…In the 1980s, several Actinomadura spp. and all Nocardiaceae species of the genus Micropolyspora were reassigned to the genera Nocardia , Nonomuraea , or Saccharopolyspora . − The complex parvodicins (similar to actaplanin, teichoplanin), macrolides, small cyclopeptides, anthracyclines, tetracenequinones, and glycosides were isolated from Nonomuraea spp. (synonym to Micropolyspora spp.)…”