Beta-lactam resistance response triggered by inactivation of a nonessential penicillin-binding protein.
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Authors
Moya, BartoloméDötsch, Andreas
Juan, Carlos
Blázquez, Jesús
Zamorano, Laura
Haussler, Susanne
Oliver, Antonio
Issue Date
2009-03
Metadata
Show full item recordAbstract
It has long been recognized that the modification of penicillin-binding proteins (PBPs) to reduce their affinity for beta-lactams is an important mechanism (target modification) by which Gram-positive cocci acquire antibiotic resistance. Among Gram-negative rods (GNR), however, this mechanism has been considered unusual, and restricted to clinically irrelevant laboratory mutants for most species. Using as a model Pseudomonas aeruginosa, high up on the list of pathogens causing life-threatening infections in hospitalized patients worldwide, we show that PBPs may also play a major role in beta-lactam resistance in GNR, but through a totally distinct mechanism. Through a detailed genetic investigation, including whole-genome analysis approaches, we demonstrate that high-level (clinical) beta-lactam resistance in vitro, in vivo, and in the clinical setting is driven by the inactivation of the dacB-encoded nonessential PBP4, which behaves as a trap target for beta-lactams. The inactivation of this PBP is shown to determine a highly efficient and complex beta-lactam resistance response, triggering overproduction of the chromosomal beta-lactamase AmpC and the specific activation of the CreBC (BlrAB) two-component regulator, which in turn plays a major role in resistance. These findings are a major step forward in our understanding of beta-lactam resistance biology, and, more importantly, they open up new perspectives on potential antibiotic targets for the treatment of infectious diseases.Citation
Beta-lactam resistance response triggered by inactivation of a nonessential penicillin-binding protein. 2009, 5 (3):e1000353 PLoS Pathog.Affiliation
Servicio de Microbiología and Unidad de Investigación, Hospital Son Dureta, Instituto Universitario de Investigación en Ciencias de la Salud Palma de Mallorca, Spain.Journal
PLoS pathogensPubMed ID
19325877Type
ArticleLanguage
enISSN
1553-7374ae974a485f413a2113503eed53cd6c53
10.1371/journal.ppat.1000353
Scopus Count
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