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Mannopeptimycins, a novel class of glycopeptide antibiotics active against gram-positive bacteria

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Abstract

Mannopeptimycins α–ɛ, novel glycopeptides with activity against methicillin-resistant staphylococci and vancomycin-resistant enterococci, are purified from the fermentation broth of a strain of Streptomyces hygroscopicus, LL-AC98, and their structures characterized using spectroscopic analyses and chemical methods. The SAR data of the natural and synthetic esters demonstrate that the presence of hydrophobic groups near the terminal mannosyl moiety is critical for antibacterial potency. Scalable syntheses of 4,6-cyclic acetals and ketals on this moiety are used to produce significant quantities of the respective mannopeptimycin derivatives. These acetal and ketal derivatives exhibit potent activities against susceptible and resistant Gram-positive bacteria in both in vitro and in vivo experiments, comparable with or exceeding the activity of vancomycin. Studies on the mechanism of action suggest that the mannopeptimycins interfere with the late stages of bacterial cell wall biosynthesis. It is believed that these antibiotics inhibit the transglycosylation by binding to the transglycosylase substrate, lipid II.

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Acknowledgements

The author wishes to thank Drs. Guy Carter, Russell Dushin, Patricia Bradford, Pete Petersen, Debra Roll, Frank Koehn, Phaik-Eng Sum, Janis Upeslacis, Tarek Mansour, and many others for their valuable comments and suggestions.

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  1. Natural Products Research, Chemical and Screening Sciences, Wyeth Research, 401 N. Middletown Road, Pearl River, NY 10965, USA

    Haiyin He

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He, H. Mannopeptimycins, a novel class of glycopeptide antibiotics active against gram-positive bacteria. Appl Microbiol Biotechnol 67, 444–452 (2005). https://doi.org/10.1007/s00253-004-1884-z

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