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Total synthesis and structure of the ramoplanin A1 and A3 aglycons: two minor components of the ramoplanin complex.

ABSTRACT: Ramoplanin is a potent antibiotic, first disclosed in 1984, that acts by inhibiting bacterial cell-wall biosynthesis. The original ramoplanin complex was shown to consist of a mixture of three closely related compounds, ramoplanin A1-A3, of which ramoplanin A2 is the most abundant. The structure of ramoplanin A2 was unambiguously established first through a series of extensive spectroscopic studies, allowing complete stereochemical assignments and subsequently providing a minor reassignment of the side-chain double-bond stereochemistry and, most recently, through total synthesis of authentic material. Here we report the total syntheses of the aglycons of the minor components of the ramoplanin complex, A1 and A3, which unambiguously establish their structure and provide an expected structural revision for the lipid side-chain double-bond stereochemistry.

SUBMITTER: Shin D

PROVIDER: S-EPMC514419 | biostudies-literature | 2004 Aug

REPOSITORIES: biostudies-literature

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Total synthesis and structure of the ramoplanin A1 and A3 aglycons: two minor components of the ramoplanin complex.

Shin Dongwoo D Rew Yosup Y Boger Dale L DL

Proceedings of the National Academy of Sciences of the United States of America 20040602 33

Ramoplanin is a potent antibiotic, first disclosed in 1984, that acts by inhibiting bacterial cell-wall biosynthesis. The original ramoplanin complex was shown to consist of a mixture of three closely related compounds, ramoplanin A1-A3, of which ramoplanin A2 is the most abundant. The structure of ramoplanin A2 was unambiguously established first through a series of extensive spectroscopic studies, allowing complete stereochemical assignments and subsequently providing a minor reassignment of t ...[more]

PMID: 15175429

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Project description:Ramoplanin is a glycolipodepsipeptide antibiotic obtained from fermentation of Actinoplanes sp. ATCC 33076 that exhibits activity against clinically important multi-drug-resistant, Gram-positive pathogens including vancomycin-resistant Enterococcus (VRE), methicillin-resistant Staphylococcus aureus (MRSA), and vancomycin-intermediate resistant Clostridium difficile. It disrupts bacterial cell wall through a unique mechanism of action by sequestering the peptidoglycan intermediate Lipid II and therefore does not show cross-resistance with other antibiotics. However, while demonstrating excellent antimicrobial activity in systemic use in animal models of infection, ramoplanin presents low local tolerability when injected intravenously. As a consequence of this limitation, new derivatives are desirable to overcome this issue. During a natural product screening program developed to discover compounds that disrupt bacterial cell wall synthesis by inhibiting peptidoglycan transglycosylation through binding to the intermediate Lipid II, 49 actinomycete strains were identified by HR-LCMS as producers of ramoplanin-related compounds. The producing strains were isolated from environmental samples collected worldwide comprising both tropical and temperate areas. To assess the diversity of this microbial population, the 49 isolates were initially identified to the genus level on the basis of their micromorphology, and 16S sequencing confirmed the initial identification of the strains. These analyses resulted in the identification of members of genus Streptomyces, as well as representatives of the families Micromonosporaceae, Nocardiaceae, Thermomonosporaceae, and Pseudonocardiaceae, suggesting that the production of ramoplanins is relatively widespread among Actinomycetes. In addition, all of these isolates were tested against a panel of Gram-positive and Gram-negative bacteria, filamentous fungi, and yeast in order to further characterize their antimicrobial properties. This work describes the diversity of actinomycete strains that produced ramoplanin-related compounds, and the analysis of the antimicrobial activity exhibited by these isolates. Our results strongly suggest the presence of new ramoplanin-analogs among these actinomycete producers.

Dataset Information

Total synthesis and structure of the ramoplanin A1 and A3 aglycons: two minor components of the ramoplanin complex.

Publications

Total synthesis and structure of the ramoplanin A1 and A3 aglycons: two minor components of the ramoplanin complex.

Similar Datasets

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