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 |
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| Médium: | Journal Article |
| Jazyk: | angličtina |
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01.08.2013
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| ISSN: | 1098-6596, 1098-6596 |
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| 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. |
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| AbstractList | 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.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. 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. |
| Author | Nithianantham, Stanley Truitt, Barbara Patel, Parita Bollinger, Lucy Yu, Guanping Delaney, Elizabeth Pesho, Michelle Khodaverdian, Varandt Jankowsky, Eckhard Shoham, Menachem |
| Author_xml | – sequence: 1 givenname: Varandt surname: Khodaverdian fullname: Khodaverdian, Varandt organization: Department of Biochemistry, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA – sequence: 2 givenname: Michelle surname: Pesho fullname: Pesho, Michelle – sequence: 3 givenname: Barbara surname: Truitt fullname: Truitt, Barbara – sequence: 4 givenname: Lucy surname: Bollinger fullname: Bollinger, Lucy – sequence: 5 givenname: Parita surname: Patel fullname: Patel, Parita – sequence: 6 givenname: Stanley surname: Nithianantham fullname: Nithianantham, Stanley – sequence: 7 givenname: Guanping surname: Yu fullname: Yu, Guanping – sequence: 8 givenname: Elizabeth surname: Delaney fullname: Delaney, Elizabeth – sequence: 9 givenname: Eckhard surname: Jankowsky fullname: Jankowsky, Eckhard – sequence: 10 givenname: Menachem surname: Shoham fullname: Shoham, Menachem |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/23689713$$D View this record in MEDLINE/PubMed |
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| SubjectTerms | 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 |
| Title | Discovery of antivirulence agents against methicillin-resistant Staphylococcus aureus |
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