Discovery of antivirulence agents against methicillin-resistant Staphylococcus aureus

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,...

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Vydáno v:Antimicrobial agents and chemotherapy Ročník 57; číslo 8; s. 3645
Hlavní autoři: Khodaverdian, Varandt, Pesho, Michelle, Truitt, Barbara, Bollinger, Lucy, Patel, Parita, Nithianantham, Stanley, Yu, Guanping, Delaney, Elizabeth, Jankowsky, Eckhard, Shoham, Menachem
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States 01.08.2013
Témata:
Animals
Bacterial Toxins - antagonists & inhibitors
Diflunisal - pharmacology
Dose-Response Relationship, Drug
Erythrocytes - drug effects
Gene Expression Regulation, Bacterial - drug effects
Hemolysin Proteins - antagonists & inhibitors
Hemolysis
Methicillin-Resistant Staphylococcus aureus - drug effects
Methicillin-Resistant Staphylococcus aureus - genetics
Microbial Sensitivity Tests
Models, Molecular
Naphthalenes - chemistry
Naphthalenes - pharmacology
Phosphorylation
Promoter Regions, Genetic
Protein Binding
Protein Structure, Tertiary
Rabbits
Transcription, Genetic
Virulence Factors - antagonists & inhibitors
ISSN:1098-6596, 1098-6596
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Shrnutí: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.
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ISSN:1098-6596
1098-6596
DOI:10.1128/AAC.00269-13