Design and Synthesis of Aryl Ether Inhibitors of the Bacillus Anthracis Enoyl‐ACP Reductase
- 11 August 2008
- journal article
- research article
- Published by Wiley in ChemMedChem
- Vol. 3 (8), 1250-1268
- https://doi.org/10.1002/cmdc.200800047
Abstract
The problem of increasing bacterial resistance to the current generation of antibiotics is well documented. Known resistant pathogens such as methicillin‐resistant Staphylococcus aureus are becoming more prevalent, while the potential exists for developing drug‐resistant pathogens for use as bioweapons, such as Bacillus anthracis. The biphenyl ether antibacterial agent, triclosan, exhibits broad‐spectrum activity by targeting the fatty acid biosynthetic pathway through inhibition of enoyl‐acyl carrier protein reductase (ENR) and provides a potential scaffold for the development of new, broad‐spectrum antibiotics. We used a structure‐based approach to develop novel aryl ether analogues of triclosan that target ENR, the product of the fabI gene, from B. anthracis (BaENR). Structure‐based design methods were used for the expansion of the compound series including X‐ray crystal structure determination, molecular docking, and QSAR methods. Structural modifications were made to both phenyl rings of the 2‐phenoxyphenyl core. A number of compounds exhibited improved potency against BaENR and increased efficacy against both the Sterne strain of B. anthracis and the methicillin‐resistant strain of S. aureus. X‐ray crystal structures of BaENR in complex with triclosan and two other compounds help explain the improved efficacy of the new compounds and suggest future rounds of optimization that might be used to improve their potency.Keywords
This publication has 61 references indexed in Scilit:
- Design and synthesis of 2-pyridones as novel inhibitors of the Bacillus anthracis enoyl-ACP reductaseBioorganic & Medicinal Chemistry Letters, 2008
- Targeting Fatty Acid Biosynthesis for the Development of Novel Chemotherapeutics against Mycobacterium tuberculosis : Evaluation of A-Ring-Modified Diphenyl Ethers as High-Affinity InhA InhibitorsAntimicrobial Agents and Chemotherapy, 2007
- In Vitro Activity of API-1252, a Novel FabI Inhibitor, against Clinical Isolates of Staphylococcus aureus and Staphylococcus epidermidisAntimicrobial Agents and Chemotherapy, 2007
- Pyrrolidine Carboxamides as a Novel Class of Inhibitors of Enoyl Acyl Carrier Protein Reductase from Mycobacterium tuberculosisJournal of Medicinal Chemistry, 2006
- Structural Basis for the Variation in Triclosan Affinity to Enoyl ReductasesJournal of Molecular Biology, 2004
- Selection of Bacillus anthracis isolates resistant to antibioticsJournal of Antimicrobial Chemotherapy, 2004
- Improved protein–ligand docking using GOLDProteins-Structure Function and Bioinformatics, 2003
- A study of the structure-activity relationship for diazaborine inhibition of Escherichia coli enoyl-ACP reductaseJournal of Molecular Biology, 2001
- Modification of the NADH of the Isoniazid Target (InhA) from Mycobacterium tuberculosisScience, 1998
- A Mechanism of Drug Action Revealed by Structural Studies of Enoyl ReductaseScience, 1996