Journal
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
Volume 53, Issue 7, Pages 2908-2917Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/AAC.01637-08
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- Agencia Nacional de Promocion Cient fica y Tecnologica (ANPCyT, Argentina)
- Consejo Nacional de Investigaciones Cient ficas y Tecnicas (CONICET)
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Metallo-beta-lactamases (M beta Ls) are zinc-dependent enzymes produced by many clinically relevant gram-negative pathogens that can hydrolyze most beta-lactam antibiotics. M beta Ls are synthesized in the bacterial cytoplasm as precursors and are secreted into the periplasm. Here, we report that the biogenesis process of the recently characterized M beta L GOB-18 demands cooperation between a main chaperone system of the bacterial cytoplasm, DnaK, and the Sec secretion machinery. Using the expression of the complete gob-18 gene from the gram-negative opportunistic pathogen Elizabethkingia meningoseptica in Escherichia coli as a model system, we found that the precursor of this metalloenzyme is secreted by the Sec pathway and reduces cell susceptibility to different beta-lactam antibiotics. Moreover, acting with different J proteins such as cytoplasmic DnaJ and membrane-associated DjlA as cochaperones, DnaK plays an essential role in the cytoplasmic transit of the GOB-18 precursor to the Sec translocon. Our studies also revealed a less relevant role, that of assisting in GOB-18 secretion, for trigger factor, while no significant functions were found for other main cytoplasmic chaperones such as SecB or GroEL/ES. The overall findings indicate that the biogenesis of GOB-18 involves cytoplasmic interaction of the precursor protein mainly with DnaK, secretion by the Sec system, and final folding and incorporation of Zn(II) ions into the bacterial periplasm.
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