A series of novel antibiotics with activity against methicillin-resistant staphylococci and vancomycin-resistant enterococci has been purified, and their structures have been characterized using spectroscopic analyses and chemical conversions. These antibiotics, designated mannopeptimycins alpha-epsilon (1-5), are glycosylated cyclic hexapeptides containing two stereoisomers of an unprecedented amino acid, alpha-amino-beta-[4'-(2'-iminoimidazolidinyl)]-beta-hydroxypropionic acid (Aiha), as a distinguishing feature. The cyclic peptide core of these antibiotics is attached to a mannosyl monosaccharide moiety in 2 and to mannosyl monosaccharide and disaccharide moieties in 1, 3, 4, and 5. The presence and position of an isovaleryl group in the terminal mannose (Man-B) in 3-5 are critical for retaining antibacterial potency.
Mannopeptimycins alpha, beta, gamma, delta, and epsilon are new cyclic glycopeptide antibiotics produced by Streptomyces hygroscopicus LL-AC98. Mannopeptimycins gamma, delta, and epsilon, which have an isovaleryl substitution at various positions on the terminal mannose of the disaccharide moiety, demonstrated moderate to good antibacterial activities. Mannopeptimycin epsilon was the most active component against methicillin-resistant staphylococci and vancomycin-resistant enterococci (MICs, 2 to 4 micro g/ml for staphylococci and streptococci and 4 to 32 micro g/ml for enterococci), while mannopeptimycins gamma and delta were two- to fourfold less active. Mannopeptimycins alpha and beta, which lack the isovaleryl substitution and the disaccharide moiety, respectively, had poor antibacterial activities. The in vivo efficacies of the mannopeptimycins in Staphylococcus aureus mouse protection studies paralleled their in vitro activities. The median effective doses of mannopeptimycins gamma, delta, and epsilon were 3.8, 2.6, and 0.59 mg/kg of body weight, respectively. The mannopeptimycins were inactive against cell wall-deficient S. aureus and caused spheroplasting of Escherichia coli imp similar to that observed with penicillin G in an osmotically protective medium. Mannopeptimycin delta rapidly inhibited [(3)H]N-acetylglucosamine incorporation into peptidoglycan in Bacillus subtilis and had no effect on DNA, RNA, or protein biosynthesis. On the basis of the observations presented above, an effect on cell wall biosynthesis was suggested as the primary mode of action for mannopeptimycin delta. The mannopeptimycins were inactive against Candida albicans, did not initiate hemolysis of human erythrocytes, and did not promote potassium ion leakage from E. coli imp, suggesting a lack of membrane damage to prokaryotic or eukaryotic cells.
The activity of LJC10,627 was compared with the activities of imipenem and other antibiotics. LJC10,627 was more active against most members of the family Enterobacteriaceae, Pseudomonas spp., and Acinetobacter spp. but slightly less active than imipenem against staphylococci and streptococci. LJC10,627 showed stability to mouse dehydropeptidase I and was more effective in vivo than imipenem plus cilastatin against gram-negative bacterial infections and as effective against staphylococcal infections.
Nitrosation, carbamoylation or acylation of the glycopeptide antibiotics eremomycin or vancomycin produced series of derivatives substituted at the N-terminus of the peptides. Though the modified amino group in these derivatives is not capable of protonation, TV-nitroso derivatives precursors to or the actual substrate for the transpeptidation reaction necessary for the formation of a rigid cell wall structure2*. The chemical modifications of eremomycin carried out in these studies were directed toward broadening the antibacterial spectrum and toward enhancement of chemotherapeutic properties3). Elucidation of structure-activity relationships in these series is also of great importance.Recently it was shown that the affinity of eremomycin for the target site mimetic diacetyl-L-lysyl-D-alanyl-D-alanine (DALAA)was 23-fold lower than that of vancomycin while the activity of eremomycin was greater than vancomycin against staphylococci and Bacillus subtilis and was less affected by DALAA than that of vancomycin40. These data demonstrate a difference of eremomycin and indicate that structure-activity relationships found for vancomycin or teicoplanin maynot be valid for eremomycin. In this paper we study the possibility of modification of eremomycin and vancomycin with nitrosating, carbamoylating or acylating agents and the structure-activity relationships amongTV-substituted derivatives of these antibiotics (Fig. 1).
ChemistryThe nitrogen atom at the TV-terminus of the peptide in eremomycinor vancomycin is designated as N, the nitrogen atom in the disaccharide branch of eremomycin (f fragment) or in vancomycin is designated as N', and the nitrogen atom in the monosaccharide branch oferemomycin (e fragment) is designated as N".TV-Nitrosated derivatives of eremomycin (II) (Scheme 1) and vancomycin (X) (Scheme 2) were prepared by the action of nitrous acid prepared in situ or by isoamylnitrite. The use of isoamylnitrite permitted the
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