title: Design and synthesis of aryl ether inhibitors of the Bacillus anthracis enoyl-ACP reductase.
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.
authors.affiliation: Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 833 S. Wood St., Chicago, IL 60612, USA.
authors.forename: Suresh K
authors.initials: SK
authors.lastname: Tipparaju
authors.forename: Debbie C
authors.initials: DC
authors.lastname: Mulhearn
authors.forename: Gary M
authors.initials: GM
authors.lastname: Klein
authors.forename: Yufeng
authors.initials: Y
authors.lastname: Chen
authors.forename: Subhasish
authors.initials: S
authors.lastname: Tapadar
authors.forename: Molly H
authors.initials: MH
authors.lastname: Bishop
authors.forename: Shuo
authors.initials: S
authors.lastname: Yang
authors.forename: Juan
authors.initials: J
authors.lastname: Chen
authors.forename: Mahmood
authors.initials: M
authors.lastname: Ghassemi
authors.forename: Bernard D
authors.initials: BD
authors.lastname: Santarsiero
authors.forename: James L
authors.initials: JL
authors.lastname: Cook
authors.forename: Mary
authors.initials: M
authors.lastname: Johlfs
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Mesecar
authors.forename: Michael E
authors.initials: ME
authors.lastname: Johnson
authors.forename: Alan P
authors.initials: AP
authors.lastname: Kozikowski
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001408:Bacillus anthracis / Q000187:drug effects* / Q000201:enzymology; D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004987:Ethers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D004987:Ethers; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)