title: Structural and biological evaluation of a novel series of benzimidazole inhibitors of Francisella tularensis enoyl-ACP reductase (FabI).
abstract: Francisella 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 Gram-negative infections. Here we report the advancement of a promising series of benzimidazole FabI (enoyl-ACP reductase) inhibitors to a second-generation using a systematic, structure-guided 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 Staphylococcus 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.
authors: Center for Pharmaceutical Biotechnology, University of Illinois at Chicago, Chicago, IL 60607, United States; Novalex Therapeutics, 2242 W. Harrison, Chicago, IL 60612, United States. Electronic address: shahila@uic.edu.
authors: Shahila
authors: S
authors: Mehboob
authors: Department of Chemistry, Purdue University, West Lafayette, IN 47907, United States; Department of Medicinal Chemistry, Purdue University, West Lafayette, IN 47907, United States.
authors: Jinhua
authors: J
authors: Song
authors: Center for Pharmaceutical Biotechnology, University of Illinois at Chicago, Chicago, IL 60607, United States.
authors: Kirk E
authors: KE
authors: Hevener
authors: Center for Pharmaceutical Biotechnology, University of Illinois at Chicago, Chicago, IL 60607, United States.
authors: Pin-Chih
authors: PC
authors: Su
authors: Center for Pharmaceutical Biotechnology, University of Illinois at Chicago, Chicago, IL 60607, United States.
authors: Teuta
authors: T
authors: Boci
authors: Center for Pharmaceutical Biotechnology, University of Illinois at Chicago, Chicago, IL 60607, United States.
authors: Libby
authors: L
authors: Brubaker
authors: Center for Pharmaceutical Biotechnology, University of Illinois at Chicago, Chicago, IL 60607, United States.
authors: Lena
authors: L
authors: Truong
authors: Center for Pharmaceutical Biotechnology, University of Illinois at Chicago, Chicago, IL 60607, United States.
authors: Tina
authors: T
authors: Mistry
authors: Division of Infectious Diseases, Loyola University Chicago, Maywood, IL 60153, United States; Edward Hines Jr. VA Hospital, Hines, IL 60141, United States.
authors: Jiangping
authors: J
authors: Deng
authors: Division of Infectious Diseases, Loyola University Chicago, Maywood, IL 60153, United States; Edward Hines Jr. VA Hospital, Hines, IL 60141, United States.
authors: James L
authors: JL
authors: Cook
authors: Center for Pharmaceutical Biotechnology, University of Illinois at Chicago, Chicago, IL 60607, United States.
authors: Bernard D
authors: BD
authors: Santarsiero
authors: Department of Chemistry, Purdue University, West Lafayette, IN 47907, United States; Department of Medicinal Chemistry, Purdue University, West Lafayette, IN 47907, United States.
authors: Arun K
authors: AK
authors: Ghosh
authors: Center for Pharmaceutical Biotechnology, University of Illinois at Chicago, Chicago, IL 60607, United States; Novalex Therapeutics, 2242 W. Harrison, Chicago, IL 60612, United States. Electronic address: mjohnson@uic.edu.
authors: Michael E
authors: ME
authors: Johnson
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D004926:Escherichia coli / Q000187:drug effects; D005604:Francisella tularensis / Q000187:drug effects / Q000201:enzymology*; D007700:Kinetics; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects; D008826:Microbial Sensitivity Tests; D056004:Molecular Dynamics Simulation; D013211:Staphylococcus aureus / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D001562:Benzimidazoles; D004791:Enzyme Inhibitors; C031000:benzimidazole; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)
keywords: Benzimidazole scaffold; Enoyl reductase; F. tularensis; FabI inhibitor; MRSA; S. aureus