title: Discovery of antivirulence agents against methicillin-resistant Staphylococcus aureus.
abstract: Antivirulence agents inhibit the production of disease-causing virulence factors but are neither bacteriostatic nor bactericidal. Antivirulence agents against methicillin-resistant Staphylococcus aureus (MRSA) strain USA300, the most widespread community-associated MRSA strain in the United States, were discovered by virtual screening against the response regulator AgrA, which acts as a transcription factor for the expression of several of the most prominent S. aureus toxins and virulence factors involved in pathogenesis. Virtual screening was followed by similarity searches in the databases of commercial vendors. The small-molecule compounds discovered inhibit the production of the toxins alpha-hemolysin and phenol-soluble modulin α in a dose-dependent manner without inhibiting bacterial growth. These antivirulence agents are small-molecule biaryl compounds in which the aromatic rings either are fused or are separated by a short linker. One of these compounds is the FDA-approved nonsteroidal anti-inflammatory drug diflunisal. This represents a new use for an old drug. Antivirulence agents might be useful in prophylaxis and as adjuvants in antibiotic therapy for MRSA infections.
authors.affiliation: Department of Biochemistry, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Varandt
authors.initials: V
authors.lastname: Khodaverdian
authors.forename: Michelle
authors.initials: M
authors.lastname: Pesho
authors.forename: Barbara
authors.initials: B
authors.lastname: Truitt
authors.forename: Lucy
authors.initials: L
authors.lastname: Bollinger
authors.forename: Parita
authors.initials: P
authors.lastname: Patel
authors.forename: Stanley
authors.initials: S
authors.lastname: Nithianantham
authors.forename: Guanping
authors.initials: G
authors.lastname: Yu
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Delaney
authors.forename: Eckhard
authors.initials: E
authors.lastname: Jankowsky
authors.forename: Menachem
authors.initials: M
authors.lastname: Shoham
mesh_terms: D000818:Animals; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors*; D004061:Diflunisal / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000187:drug effects; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects; D006460:Hemolysin Proteins / Q000037:antagonists & inhibitors*; D006461:Hemolysis; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects* / Q000235:genetics; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D009281:Naphthalenes / Q000737:chemistry / Q000494:pharmacology; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011817:Rabbits; D014158:Transcription, Genetic; D037521:Virulence Factors / Q000037:antagonists & inhibitors*
chemical_list: D001427:Bacterial Toxins; D006460:Hemolysin Proteins; D009281:Naphthalenes; D037521:Virulence Factors; C021091:staphylococcal alpha-toxin; C025971:staphylococcal delta toxin; D004061:Diflunisal