title: Repurposing the antihistamine terfenadine for antimicrobial activity against Staphylococcus aureus.
abstract: Staphylococcus aureus is a rapidly growing health threat in the U.S., with resistance to several commonly prescribed treatments. A high-throughput screen identified the antihistamine terfenadine to possess, previously unreported, antimicrobial activity against S. aureus and other Gram-positive bacteria. In an effort to repurpose this drug, structure-activity relationship studies yielded 84 terfenadine-based analogues with several modifications providing increased activity versus S. aureus and other bacterial pathogens, including Mycobacterium tuberculosis. Mechanism of action studies revealed these compounds to exert their antibacterial effects, at least in part, through inhibition of the bacterial type II topoisomerases. This scaffold suffers from hERG liabilities which were not remedied through this round of optimization; however, given the overall improvement in activity of the set, terfenadine-based analogues provide a novel structural class of antimicrobial compounds with potential for further characterization as part of the continuing process to meet the current need for new antibiotics.
authors.affiliation: Department of Microbiology and Immunology, University of Rochester Medical Center , 601 Elmwood Avenue, Rochester, New York 14642, United States.
authors.forename: Jessamyn I
authors.initials: JI
authors.lastname: Perlmutter
authors.forename: Lauren T
authors.initials: LT
authors.lastname: Forbes
authors.forename: Damian J
authors.initials: DJ
authors.lastname: Krysan
authors.forename: Katherine
authors.initials: K
authors.lastname: Ebsworth-Mojica
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Colquhoun
authors.forename: Jenna L
authors.initials: JL
authors.lastname: Wang
authors.forename: Paul M
authors.initials: PM
authors.lastname: Dunman
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Flaherty
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D060326:Chemistry Techniques, Synthetic; D027081:DNA Gyrase / Q000737:chemistry / Q000378:metabolism; D027101:DNA Topoisomerase IV / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D039563:Histamine H1 Antagonists, Non-Sedating / Q000737:chemistry; D006801:Humans; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000201:enzymology; D013329:Structure-Activity Relationship; D016593:Terfenadine / Q000031:analogs & derivatives / Q000737:chemistry*; D059005:Topoisomerase II Inhibitors / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D039563:Histamine H1 Antagonists, Non-Sedating; C000606913:KCNH2 protein, human; D059005:Topoisomerase II Inhibitors; D016593:Terfenadine; D027101:DNA Topoisomerase IV; D027081:DNA Gyrase