2QIO

X-Ray Structure of Enoyl-Acyl Carrier Protein Reductase from Bacillus Anthracis with Triclosan

Summary for 2QIO

• Entry DOI: 10.2210/pdb2qio/pdb
• Related: 1d7o 1d8a 1nhg 2o2s
• Descriptor: Enoyl-(Acyl-carrier-protein) reductase, NICOTINAMIDE-ADENINE-DINUCLEOTIDE, TRICLOSAN, ... (4 entities in total)
• Functional Keywords: enoyl acp reductase, unknown function
• Biological source: Bacillus anthracis
• Total number of polymer chains: 4
• Total formula weight: 114901.57

Authors

Klein, G.M.,Santarsiero, B.D.,Mesecar, A.D. (deposition date: 2007-07-05, release date: 2008-07-08, Last modification date: 2023-08-30)

Primary citation

Tipparaju, S.K.,Mulhearn, D.C.,Klein, G.M.,Chen, Y.,Tapadar, S.,Bishop, M.H.,Yang, S.,Chen, J.,Ghassemi, M.,Santarsiero, B.D.,Cook, J.L.,Johlfs, M.,Mesecar, A.D.,Johnson, M.E.,Kozikowski, A.P.
Design and synthesis of aryl ether inhibitors of the Bacillus anthracis enoyl-ACP reductase.
Chemmedchem, 3:1250-1268, 2008

PubMed 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.

PubMed: 18663709
DOI: 10.1002/cmdc.200800047

Experimental method

X-RAY DIFFRACTION (2.44 Å)