Affiliation:
1. Natural Products Microbiology
2. Antibacterial Research, Infectious Disease Section, Wyeth Research, Pearl River, New York 10965
Abstract
ABSTRACT
Mannopeptimycins α, β, γ, δ, and ε are new cyclic glycopeptide antibiotics produced by
Streptomyces hygroscopicus
LL-AC98. Mannopeptimycins γ, δ, and ε, which have an isovaleryl substitution at various positions on the terminal mannose of the disaccharide moiety, demonstrated moderate to good antibacterial activities. Mannopeptimycin ε was the most active component against methicillin-resistant staphylococci and vancomycin-resistant enterococci (MICs, 2 to 4 μg/ml for staphylococci and streptococci and 4 to 32 μg/ml for enterococci), while mannopeptimycins γ and δ were two- to fourfold less active. Mannopeptimycins α and β, 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 γ, δ, and ε 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 δ 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 δ. 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.
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology
Reference16 articles.
1. Barbosa, M. D. F. S., G. Yang, J. Fang, M. G. Kurilla, and D. L. Pompliano. 2002. Development of a whole-cell assay for peptidoglycan biosynthesis inhibitor. Antimicrob. Agents Chemother.40:943-946.
2. Bonomo, R. A. 2000. Multiple antibiotic-resistant bacteria in long-term-care facilities: an emerging problem in the practice of infectious diseases. Clin. Infect. Dis.31:1414-1422.
3. Vancomycin-Resistant Enterococci
4. The search for antimicrobial agents effective against bacteria resistant to multiple antibiotics
5. Gerberding J. L. 2000. CDC semiannual report: aggregate data from the national infection surveillance (NNIS) system. U.S. Department of Health and Human Services Atlanta Ga.