Beta-lactam resistance response triggered by inactivation of a nonessential penicillin-binding protein.

2.50
Hdl Handle:
http://hdl.handle.net/10033/70595
Title:
Beta-lactam resistance response triggered by inactivation of a nonessential penicillin-binding protein.
Authors:
Moya, Bartolomé; Dötsch, Andreas; Juan, Carlos; Blázquez, Jesús; Zamorano, Laura; Haussler, Susanne; Oliver, Antonio
Abstract:
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.
Affiliation:
Servicio de Microbiología and Unidad de Investigación, Hospital Son Dureta, Instituto Universitario de Investigación en Ciencias de la Salud Palma de Mallorca, Spain.
Citation:
Beta-lactam resistance response triggered by inactivation of a nonessential penicillin-binding protein. 2009, 5 (3):e1000353 PLoS Pathog.
Journal:
PLoS pathogens
Issue Date:
Mar-2009
URI:
http://hdl.handle.net/10033/70595
DOI:
10.1371/journal.ppat.1000353
PubMed ID:
19325877
Type:
Article
Language:
en
ISSN:
1553-7374
Appears in Collections:
publications of the research group chronic pseudomonas infections (CPI)

Full metadata record

DC FieldValue Language
dc.contributor.authorMoya, Bartolomé-
dc.contributor.authorDötsch, Andreas-
dc.contributor.authorJuan, Carlos-
dc.contributor.authorBlázquez, Jesús-
dc.contributor.authorZamorano, Laura-
dc.contributor.authorHaussler, Susanne-
dc.contributor.authorOliver, Antonio-
dc.date.accessioned2009-06-16T13:05:46Z-
dc.date.available2009-06-16T13:05:46Z-
dc.date.issued2009-03-
dc.identifier.citationBeta-lactam resistance response triggered by inactivation of a nonessential penicillin-binding protein. 2009, 5 (3):e1000353 PLoS Pathog.en
dc.identifier.issn1553-7374-
dc.identifier.pmid19325877-
dc.identifier.doi10.1371/journal.ppat.1000353-
dc.identifier.urihttp://hdl.handle.net/10033/70595-
dc.description.abstractIt 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.en
dc.language.isoenen
dc.subject.meshAnimalsen
dc.subject.meshBacterial Proteinsen
dc.subject.meshComparative Genomic Hybridizationen
dc.subject.meshGene Expressionen
dc.subject.meshGene Expression Regulation, Bacterialen
dc.subject.meshHumansen
dc.subject.meshMiceen
dc.subject.meshMutationen
dc.subject.meshOligonucleotide Array Sequence Analysisen
dc.subject.meshPenicillin-Binding Proteinsen
dc.subject.meshPseudomonas aeruginosaen
dc.subject.meshReverse Transcriptase Polymerase Chain Reactionen
dc.subject.meshbeta-Lactam Resistanceen
dc.subject.meshbeta-Lactamasesen
dc.titleBeta-lactam resistance response triggered by inactivation of a nonessential penicillin-binding protein.en
dc.typeArticleen
dc.contributor.departmentServicio de Microbiología and Unidad de Investigación, Hospital Son Dureta, Instituto Universitario de Investigación en Ciencias de la Salud Palma de Mallorca, Spain.en
dc.identifier.journalPLoS pathogensen

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