Discovery and analysis of 4H-Pyridopyrimidines, a class of selective bacterial protein synthesis inhibitors

Authors

• Wendy Ribble, Replidyne, Inc.
• Walter E. Hill, University of Montana
• Urs A. Ochsner, Replidyne, Inc.
• Thale C. Jarvis, Replidyne, Inc.
• Joseph W. Guiles, Replidyne, Inc.
• Nebojsa Janjic, Replidyne, Inc.
• James M. Bullard, The University of Texas Rio Grande ValleyFollow

Document Type

Article

Publication Date

11-1-2010

Abstract

Bacterial protein synthesis is the target for numerous natural and synthetic antibacterial agents. We have developed a poly(U) mRNA-directed aminoacylation/translation protein synthesis system composed of phenyltRNA synthetases, ribosomes, and ribosomal factors from Escherichia coli. This system, utilizing purified components, has been used for high-throughput screening of a small-molecule chemical library. We have identified a series of compounds that inhibit protein synthesis with 50% inhibitory concentrations (IC50s) ranging from 3 to 14 μM. This series of compounds all contained the same central scaffold composed of tetrahydropyrido[4,3-d] pyrimidin-4-ol (e.g., 4H-pyridopyrimidine). All analogs contained an ortho pyridine ring attached to the central scaffold in the 2 position and either a five- or a six-member ring tethered to the 6-methylene nitrogen atom of the central scaffold. These compounds inhibited the growth of E. coli, Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis, with MICs ranging from 0.25 to 32 μg/ml. Macromolecular synthesis (MMS) assays with E. coli and S. aureus confirmed that antibacterial activity resulted from specific inhibition of protein synthesis. Assays were developed for the steps performed by each component of the system in order to ascertain the target of the compounds, and the ribosome was found to be the site of inhibition. Copyright © 2010, American Society for Microbiology. All Rights Reserved.

Comments

© 2010, American Society for Microbiology. All Rights Reserved.

Recommended Citation

Ribble, Wendy, Walter E. Hill, Urs A. Ochsner, Thale C. Jarvis, Joseph W. Guiles, Nebojsa Janjic, and James M. Bullard. "Discovery and analysis of 4 H-Pyridopyrimidines, a class of selective bacterial protein synthesis inhibitors." Antimicrobial agents and chemotherapy 54, no. 11 (2010): 4648-4657. https://doi.org/10.1128/AAC.00638-10

First Page

4648

Last Page

4657

Publication Title

Antimicrobial Agents and Chemotherapy

DOI

10.1128/AAC.00638-10