Mannopeptimycins, new cyclic glycopeptide antibiotics produced by Streptomyces hygroscopicus LL-AC98: antibacterial and mechanistic activities

Abstract

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.

FIG. 1.

Chemical structures of mannopeptimycins α, β, γ, δ, and ɛ.

FIG. 1.

Chemical structures of mannopeptimycins α, β, γ, δ, and ɛ.

FIG. 2.

Bactericidal activities of mannopeptimycin δ (•, ▪, ▴) and vancomycin (○) against S. aureus 375.

FIG. 3.

Spheroplasting activities of mannopeptimycin δ and other cell wall-active agents.

FIG. 4.

Growth curves of S. aureus 375 (Sa375) and S. aureus 375M40 (Sa375M40). OD, optical density.