Structural and biological evaluation of a novel series of benzimidazole inhibitors of Francisella tularensis enoyl-ACP reductase (FabI).
journal contribution
posted on 2018-01-15, 00:00 authored by S. Mehboob, J. Song, K.E. Hevener, P-C. Su, T. Boci, L. Brubaker, L. TruongFrancisella tularensis, the causative agent of tularemia, presents a significant biological threat
and is a Category A priority pathogen due to its potential for weaponization. The bacterial FASII
pathway is a viable target for the development of novel antibacterial agents treating Gramnegative
infections. Here we report the advancement of a promising series of benzimidazole
FabI (enoyl-ACP reductase) inhibitors to a second-generation using a systematic, structureguided
lead optimization strategy, and the determination of several co-crystal structures that
confirm the binding mode of designed inhibitors. These compounds display an improved low
nanomolar enzymatic activity as well as promising low microgram/mL antibacterial activity
against both F. tularensis and S. aureus and its methicillin-resistant strain (MRSA). The
improvements in activity accompanying structural modifications lead to a better understanding
of the relationship between the chemical structure and biological activity that encompasses
both enzymatic and whole-cell activity.
Funding
This work was supported in part by National Institutes of Health Grants U01-AI077949 and R41AI110090. K.E.H. was supported during a portion of this work by NIDCR 5T32-DE018381, UIC College of Dentistry, MOST Program. P.C.S was supported by 13PRE14800030, a predoctoral fellowship from the American Heart Association, the Mid-West Affiliate. B.D.S was supported in part by the UIC Center for Clinical and Translational Science through grant UL1TR000050 from the National Institutes of Health. Use of the Advanced Photon Source was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. DE-AC02-06CH11357. Use of the LS-CAT Sector 21 was supported by the Michigan Economic Development Corporation and the Michigan Technology Tri-Corridor for the support of this research program (Grant 085P1000817). ChemDraw was used for drawing and displaying chemical structures (ChemDraw v13.0, CambridgeSoft Corp.). Molecular graphics and analyses were performed with the UCSF Chimera package. Chimera is developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco (supported by NIGMS P41-GM103311).
History
Publisher Statement
This is the author’s version of a work that was accepted for publication in Bioorganic and Medicinal Chemistry Letters. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Bioorganic and Medicinal Chemistry Letters, [Vol 25, Issue 6, (2015)] DOI:10.1016/j.bmcl.2015.01.048.Publisher
Elsevier Inc.issn
0960-894XIssue date
2015-03-15Usage metrics
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