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Antimicrobial Agents and Chemotherapy, January 2003, p. 62-69, Vol. 47, No. 1
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.1.62-69.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Mannopeptimycins, New Cyclic Glycopeptide Antibiotics Produced by Streptomyces hygroscopicus LL-AC98: Antibacterial and Mechanistic Activities

M. P. Singh,1* P. J. Petersen,2 W. J. Weiss,2 J. E. Janso,1 S. W. Luckman,1 E. B. Lenoy,2 P. A. Bradford,2 R. T. Testa,1,2 and M. Greenstein1

Natural Products Microbiology,1 Antibacterial Research, Infectious Disease Section, Wyeth Research, Pearl River, New York 109652

Received 2 May 2002/ Returned for modification 6 August 2002/ Accepted 21 September 2002

Mannopeptimycins {alpha}, ß, {gamma}, {delta}, and {varepsilon} are new cyclic glycopeptide antibiotics produced by Streptomyces hygroscopicus LL-AC98. Mannopeptimycins {gamma}, {delta}, and {varepsilon}, which have an isovaleryl substitution at various positions on the terminal mannose of the disaccharide moiety, demonstrated moderate to good antibacterial activities. Mannopeptimycin {varepsilon} 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 {gamma} and {delta} were two- to fourfold less active. Mannopeptimycins {alpha} and ß, 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 {varepsilon} 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 [3H]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.

* Corresponding author. Mailing address: Natural Products Microbiology, Wyeth Research, 401 N. Middletown Rd., Bldg./Rm. 205/457, Pearl River, NY 10965. Phone: (845) 602-4869. Fax: (845) 602-5687. E-mail: singhm{at}wyeth.com.

Antimicrobial Agents and Chemotherapy, January 2003, p. 62-69, Vol. 47, No. 1
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.1.62-69.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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