Inhibition of WTA synthesis blocks the cooperative action of PBPs and sensitizes MRSA to ß-lactams.
ACS Chem Biol
; 8(1): 226-33, 2013 Jan 18.
Article
en En
| MEDLINE
| ID: mdl-23062620
ABSTRACT
Rising drug resistance is limiting treatment options for infections by methicillin-resistant Staphylococcus aureus (MRSA). Herein we provide new evidence that wall teichoic acid (WTA) biogenesis is a remarkable antibacterial target with the capacity to destabilize the cooperative action of penicillin-binding proteins (PBPs) that underlie ß-lactam resistance in MRSA. Deletion of gene tarO, encoding the first step of WTA synthesis, resulted in the restoration of sensitivity of MRSA to a unique profile of ß-lactam antibiotics with a known selectivity for penicillin binding protein 2 (PBP2). Of these, cefuroxime was used as a probe to screen for previously approved drugs with a cryptic capacity to potentiate its activity against MRSA. Ticlopidine, the antiplatelet drug Ticlid, strongly potentiated cefuroxime, and this synergy was abolished in strains lacking tarO. The combination was also effective in a Galleria mellonella model of infection. Using both genetic and biochemical strategies, we determined the molecular target of ticlopidine as the N-acetylglucosamine-1-phosphate transferase encoded in gene tarO and provide evidence that WTA biogenesis represents an Achilles heel supporting the cooperative function of PBP2 and PBP4 in creating highly cross-linked muropeptides in the peptidoglycan of S. aureus. This approach represents a new paradigm to tackle MRSA infection.
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1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Ácidos Teicoicos
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Pared Celular
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Beta-Lactamas
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Proteínas de Unión a las Penicilinas
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Staphylococcus aureus Resistente a Meticilina
Idioma:
En
Revista:
ACS Chem Biol
Año:
2013
Tipo del documento:
Article