No abstract

Three new glycopeptide antibiotics, aridicins A, B, and C, produced by Kibdelosporangium aridum have a spectrum of antimicrobial activity in vitro which is similar to that of vancomycin. The antimicrobial activities of these glycopeptides against clinical bacterial isolates were compared with those of vancomycin and other related glycopeptide antibiotics in vitro by agar dilution and microtiter broth dilution tests and in vivo in mouse protection studies. In vitro they were somewhat less effective than vancomycin against strains of Staphylococcus aureus and less active against coagulase-negative Staphylococcus spp. However, they were more active than vancomycin against strains of Streptococcus faecalis and markedly superior to vancomycin and other glycopeptide antibiotics against strains of Clostridium difficile. In experimental infections, aridicin A was effective against strains of S. aureus, S. epidermidis, Streptococcus faecalis, and Streptococcus pyogenes, although its 50% effective doses were higher than those of vancomycin when administered after infection. After subcutaneous administration, aridicin A had a higher peak level in serum and a longer half-life than vancomycin or teicoplanin. The aridicins were markedly superior to vancomycin when administered prior to infection in mouse protection tests, indicating long-acting potential.Aridicins are glycopeptide antibiotics of the vancomycin class which are produced by a new genus of the order Actinomycetales, Kibdelosporangiium aridum ATCC 39922. The production, isolation, spectrum of activity, and chemical characterization of these antibiotics have been reported previously (8, 9). These glycopeptides differ from most members of this class, with the exception of teicoplanin (1). Both the aridicins and teicoplanin (teichomycin) possess a glycolipid constituent and have an acidic isoelectric point. The spectrum of antimicrobial activity in vitro for all of the glycopeptides reported in the literature is similar to that of vancomycin and is limited, probably owing to their molecular size, to gram-positive bacteria (10-12). The microbiological and pharmacokinetic properties of the aridicins were compared with those of vancomycin and other members of this class of antibiotics. MATERIALS AND METHODS Antibiotics

Chlorocardicin is a new monocyclic (l-lactam produced by a Streptomyces sp. It is structurally related to nocardicin A but differs in having a m-chloro substituent on the phydroxyphenylglycine unit. The biological activity of chlorocardicin was similar to nocardicin A but the former showed less antagonism in complex media. Moderate in vitro activity was observed against Enterobacteriaceae and Pseudomonas aeruginosa. Chlorocardicin showed low activity against Staphylococcus aureus whereas nocardicin A was inactive. Both compounds were shown to be strongly potentiated by antibiotics that inhibit peptidoglycan biosynthesis and were antagonized by selected Land D-amino acids.

Alafosfalin, an antibacterial phosphonodipeptide requiring peptide transport for activity, was tested for activity against clinical strains of anaerobic bacteria in peptide-free Roche Sensitivity Test Medium no. 5 agar. It was active against Bacteroides spp., Fusobacterium nucleatum, and Clostridium perfringens but not against Clostridium difficile. Alafosfalin activity was antagonized by appropriate peptides. Synergy was obtained with other cell wall-active antibiotics.

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