Journal article
Repurposing the Antihistamine Terfenadine for Antimicrobial Activity against Staphylococcus aureus
Journal of medicinal chemistry, Vol.57(20), pp.8540-8562
10/23/2014
DOI: 10.1021/jm5010682
PMCID: PMC4207543
PMID: 25238555
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.
Details
- Title: Subtitle
- Repurposing the Antihistamine Terfenadine for Antimicrobial Activity against Staphylococcus aureus
- Creators
- Jessamyn I Perlmutter - Department of Microbiology and ImmunologyDamian J Krysan - Department of PediatricsLauren T Forbes - Department of Microbiology and ImmunologyKatherine Ebsworth-Mojica - Department of Microbiology and ImmunologyJennifer M Colquhoun - Department of Microbiology and ImmunologyJenna L Wang - Specialized Chemistry Center, Delbert M. Shankel Structural Biology CenterPaul M Dunman - Department of Microbiology and ImmunologyDaniel P Flaherty - Specialized Chemistry Center, Delbert M. Shankel Structural Biology Center
- Resource Type
- Journal article
- Publication Details
- Journal of medicinal chemistry, Vol.57(20), pp.8540-8562
- Publisher
- American Chemical Society
- DOI
- 10.1021/jm5010682
- PMID
- 25238555
- PMCID
- PMC4207543
- ISSN
- 0022-2623
- eISSN
- 1520-4804
- Language
- English
- Date published
- 10/23/2014
- Academic Unit
- Microbiology and Immunology; Stead Family Department of Pediatrics; Infectious Disease (Pediatrics)
- Record Identifier
- 9984093358002771
Metrics
24 Record Views