Diversity-oriented synthesis of cyclic acyldepsipeptides leads to the discovery of a potent antibacterial agent
Document Type
Article
Date of Original Version
10-15-2010
Abstract
A class of cyclic acyldepsipeptide antibiotics collectively known as the enopeptins has recently attracted much attention because of their activity against multidrug-resistant bacteria, including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecalis. These antibiotics are further distinguished by their novel mechanism of action in which they bind and deregulate the tightly controlled activity of the cytoplasmic protease ClpP. Although the natural products have poor pharmacological properties, a synthetic derivative called acyldepsipeptide 4 (ADEP 4) showed remarkable antibacterial activity both in vitro and in mouse models of bacterial infections. A novel route to the ADEP 4 peptidolactone core structure, featuring the Joullié-Ugi three-component reaction, was developed. This multicomponent reaction and a related multicomponent reaction, the Ugi four-component reaction, were used to prepare analogs that were designed using the principles of conformational analysis. These cyclic acyldepsipeptides were tested for their activity against drug-resistant, clinical isolates of Staphylococci and Enterococci. One ADEP 4 analog in which the pipecolate was replaced by 4-methyl pipecolate exhibited in vitro antibacterial activity against Enterococci that was fourfold higher than the parent compound. © 2010 Elsevier Ltd. All rights reserved.
Publication Title, e.g., Journal
Bioorganic and Medicinal Chemistry
Volume
18
Issue
20
Citation/Publisher Attribution
Socha, Aaron M., Y. Tan, Kerry L. Laplante, and Jason K. Sello. "Diversity-oriented synthesis of cyclic acyldepsipeptides leads to the discovery of a potent antibacterial agent." Bioorganic and Medicinal Chemistry 18, 20 (2010): 7193-7202. doi: 10.1016/j.bmc.2010.08.032.