Antiinfective therapy with a small molecule inhibitor of Staphylococcus aureus sortase.
Proc Natl Acad Sci U S A
; 111(37): 13517-22, 2014 Sep 16.
Article
em En
| MEDLINE
| ID: mdl-25197057
ABSTRACT
Methicillin-resistant Staphylococcus aureus (MRSA) is the most frequent cause of hospital-acquired infection, which manifests as surgical site infections, bacteremia, and sepsis. Due to drug-resistance, prophylaxis of MRSA infection with antibiotics frequently fails or incites nosocomial diseases such as Clostridium difficile infection. Sortase A is a transpeptidase that anchors surface proteins in the envelope of S. aureus, and sortase mutants are unable to cause bacteremia or sepsis in mice. Here we used virtual screening and optimization of inhibitor structure to identify 3-(4-pyridinyl)-6-(2-sodiumsulfonatephenyl)[1,2,4]triazolo[3,4-b][1,3,4]thiadiazole and related compounds, which block sortase activity in vitro and in vivo. Sortase inhibitors do not affect in vitro staphylococcal growth yet protect mice against lethal S. aureus bacteremia. Thus, sortase inhibitors may be useful as antiinfective therapy to prevent hospital-acquired S. aureus infection in high-risk patients without the side effects of antibiotics.
Palavras-chave
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Inibidores de Proteases
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Staphylococcus aureus
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Proteínas de Bactérias
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Aminoaciltransferases
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Bibliotecas de Moléculas Pequenas
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Anti-Infecciosos
Limite:
Animals
Idioma:
En
Revista:
Proc Natl Acad Sci U S A
Ano de publicação:
2014
Tipo de documento:
Article