title: Benzimidazole-Based FabI Inhibitors: A Promising Novel Scaffold for Anti-staphylococcal Drug Development.
abstract: The enoyl-ACP reductase (FabI) enzyme is a well validated target for anti-staphylococcal drug discovery and development. With the goal of finding alternate therapeutics for drug-resistant strains of Staphylococcus aureus, such as methicillin-resistant S. aureus (MRSA), our previously published series of benzimidazole-based inhibitors of the FabI enzyme from Francisella tularensis (FtFabI) have been evaluated against FabI from S. aureus (SaFabI). We report here the preliminary structure-activity relationship of this series and the prioritization of compounds toward lead optimization. Mutational studies have identified key residues that contribute toward stabilizing the inhibitors in the active site of FabI. Mutations that do not significantly impact enzyme function but destabilize inhibitor binding are more likely to occur in nature as organisms evolve to evade the action of antibiotics leading to resistance. Identifying these residues provides guidance for minimizing susceptibility to resistance. Additionally, we have identified compounds that elicit antibacterial activity through off-target effects and observe that close analogs can display differing modes of action (on-target vs off-target) and need to be individually evaluated early on to prioritize compounds for lead optimization. Overall, our data suggest that the benzimidazole scaffold is a promising scaffold for anti-staphylococcal drug development.
authors.affiliation: Center for Biomolecular Sciences, University of Illinois at Chicago , Chicago, Illinois 60607, United States.
authors.forename: Tina L
authors.initials: TL
authors.lastname: Mistry
authors.affiliation: Center for Biomolecular Sciences, University of Illinois at Chicago , Chicago, Illinois 60607, United States.
authors.forename: Lena
authors.initials: L
authors.lastname: Truong
authors.affiliation: Department of Chemistry, Purdue University , West Lafayette, Indiana 47907, United States.
authors.forename: Arun K
authors.initials: AK
authors.lastname: Ghosh
authors.affiliation: Center for Biomolecular Sciences, University of Illinois at Chicago , Chicago, Illinois 60607, United States.|Novalex Therapeutics , 2242 W. Harrison, Chicago, Illinois 60612, United States.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Johnson
authors.affiliation: Novalex Therapeutics , 2242 W. Harrison, Chicago, Illinois 60612, United States.
authors.forename: Shahila
authors.initials: S
authors.lastname: Mehboob
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001562:Benzimidazoles / Q000737:chemistry* / Q000494:pharmacology*; D003001:Cloning, Molecular; D015195:Drug Design; D055808:Drug Discovery; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D013211:Staphylococcus aureus / Q000187:drug effects / Q000201:enzymology*; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D001562:Benzimidazoles; D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH)
keywords: FabI; Staphylococcus aureus; benzimidazole inhibitor; enoyl-ACP reductase; mode of action