Discovery of Novel Disaccharide Antibacterial Agents Using a Combinatorial Library Approach
| Autor: | Rui Liang, Chunguang Wang, Kiho Han, Nicole T. Hatzenbuhler, Buwen Huang, Muthoni G. Kamau, Helena R. Axelrod, Jan A. Anderson, Ramesh Kakarla, Neil Bristol, Anna Chen, Domingos J. Silva, Arthur Branstrom, Robert D. Goldman, Richard G. Dulina, Huiming Wang, Feng Chi, David Gange, Clifford B. Longley, Michael J. Sofia, Nigel M. Allanson, Dashan Liu, Rakesh K. Jain, Eugene R. Baizman, Natan A. Kogan, Sunita Midha |
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| Rok vydání: | 1999 |
| Předmět: |
Glycan
Natural product Bacteria biology Disaccharide Drug Resistance Microbial Biological activity Disaccharides Bacterial cell structure Anti-Bacterial Agents Cell wall Structure-Activity Relationship chemistry.chemical_compound Biochemistry chemistry Cell Wall Drug Discovery biology.protein Molecular Medicine Peptidoglycan Antibacterial agent |
| Zdroj: | Journal of Medicinal Chemistry. 42:3193-3198 |
| ISSN: | 1520-4804 0022-2623 6492-7660 |
| Popis: | The increase in bacterial resistance to conventional chemotherapy has resulted in a resurgent interest in the discovery and development of antibacterial agents.1-4 The search for novel antibiotics active against resistant phenotypes is increasingly focused on identification of novel chemotypes or antibiotics with novel mechanisms of action.5,6 The bacterial cell wall is an attractive target for developing novel antibacterial agents. The cell wall of both Gram-positive and Gram-negative bacteria is essential for cell viability. Of the many enzymes involved in bacterial cell wall biosynthesis, only transpeptidases responsible for cross-linking the growing glycan chain are targeted by existing clinically useful chemotherapeutic agents. As a strategy for developing novel antibacterial agents that would be effective against resistant phenotypes, we focused on the transglycosylase enzyme activity associated with the penicillin-binding proteins (PBPs). This activity functions to lengthen the peptidoglycan polymer and may also be required to initiate synthesis of a new chain. Our approach for developing novel inhibitors of transglycosylase focused on exploring moenomycin A (1) (Chart 1) as a lead. The moenomycins are a family of natural product antibiotics which are known to inhibit the synthesis of bacterial cell wall peptidoglycan through inhibition of transglycosylase.7-11 Moenomycin A is a pentasaccharide containing a long lipid attached to the reducing sugar (F) through a phosphoglycerate unit. By degradation studies and limited directed analogue synthesis, Welzel and co-workers showed that cell wall inhibitory activity was retained in a disaccharide core structure 2.12-22 In addition, they showed that certain structural elements were important for retaining transglycosylase inhibitory activity. The activity of moenomycin-derived disaccharides encouraged us to investigate the construction and screening of a library of disaccharides related to moenomycin A with the goal of identifying novel bacterial transglycosylase inhibitors. Access to a library of moenomycin disaccharides required that we develop a general solid-phase synthetic strategy that would allow us to explore carbohydrate diversity and chemical diversity at sites known to be linked to biological activity. Welzel had shown that the carbamate at C-3, the amide at C-2′, and the phosphoglycerate moiety at C-1 were important in overall biological activity.12-22 However, structural variations at these sites were never explored. The complexity of the moenomycin disaccharide system in combination with our desire to investigate multiple structural variations combinatorially posed a formidable synthetic challenge. Although solution syntheses of several moenomycin-type disaccharides had been reported by Welzel and others, these syntheses lacked the generality and efficiencynecessaryforconstructingcomplexlibraries.12-22 In this paper, we describe the solid-phase synthesis of a library of moenomycin disaccharide analogues and the identification of novel antibacterial agents from this library. Our basic synthetic approach envisioned constructing appropriately functionalized and protected disaccharide lactols that would allow us to explore modifications at C-1, C-3, and C-2′ and explore limited variation in the * Address for correspondence: Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, P.O. Box 5100, Wallingford, CT 06492-7660. E-mail: sofiam@bms.com. © Copyright 1999 by the American Chemical Society |
| Databáze: | OpenAIRE |
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