Discovery of potent wall teichoic acid early stage inhibitors.
Bioorg Med Chem Lett
; 26(16): 3999-4002, 2016 08 15.
Article
em En
| MEDLINE
| ID: mdl-27436582
ABSTRACT
The widespread emergence of methicillin-resistant Staphylococcus aureus (MRSA) has dramatically eroded the efficacy of current ß-lactam antibiotics and created an urgent need for novel treatment options. Using an S. aureus phenotypic screening strategy, we have identified small molecule early stage wall teichoic acid (WTA) pathway-specific inhibitors predicted to be chemically synergistic with ß-lactams. These previously disclosed inhibitors, termed tarocins, demonstrate by genetic and biochemical means inhibition of TarO, the first step in WTA biosynthesis. Tarocins demonstrate potent bactericidal synergy in combination with broad spectrum ß-lactam antibiotics across diverse clinical isolates of methicillin-resistant Staphylococci. The synthesis and structure-activity relationships (SAR) of a tarocin series will be detailed. Tarocins and other WTA inhibitors may provide a rational strategy to develop Gram-positive bactericidal ß-lactam combination agents active against methicillin-resistant Staphylococci.
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1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Ácidos Teicoicos
/
Beta-Lactamas
/
Antibacterianos
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article