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

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 be...

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Autores principales:	Bartolomé Moya, Andreas Dötsch, Carlos Juan, Jesús Blázquez, Laura Zamorano, Susanne Haussler, Antonio Oliver
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2009
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/883ebeaab7214dfd9cdd68b724abc5e4
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spelling	oai:doaj.org-article:883ebeaab7214dfd9cdd68b724abc5e42021-11-25T05:47:11ZBeta-lactam resistance response triggered by inactivation of a nonessential penicillin-binding protein.1553-73661553-737410.1371/journal.ppat.1000353https://doaj.org/article/883ebeaab7214dfd9cdd68b724abc5e42009-03-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19325877/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374It 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.Bartolomé MoyaAndreas DötschCarlos JuanJesús BlázquezLaura ZamoranoSusanne HausslerAntonio OliverPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 5, Iss 3, p e1000353 (2009)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Bartolomé Moya Andreas Dötsch Carlos Juan Jesús Blázquez Laura Zamorano Susanne Haussler Antonio Oliver Beta-lactam resistance response triggered by inactivation of a nonessential penicillin-binding protein.
description	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.
format	article
author	Bartolomé Moya Andreas Dötsch Carlos Juan Jesús Blázquez Laura Zamorano Susanne Haussler Antonio Oliver
author_facet	Bartolomé Moya Andreas Dötsch Carlos Juan Jesús Blázquez Laura Zamorano Susanne Haussler Antonio Oliver
author_sort	Bartolomé Moya
title	Beta-lactam resistance response triggered by inactivation of a nonessential penicillin-binding protein.
title_short	Beta-lactam resistance response triggered by inactivation of a nonessential penicillin-binding protein.
title_full	Beta-lactam resistance response triggered by inactivation of a nonessential penicillin-binding protein.
title_fullStr	Beta-lactam resistance response triggered by inactivation of a nonessential penicillin-binding protein.
title_full_unstemmed	Beta-lactam resistance response triggered by inactivation of a nonessential penicillin-binding protein.
title_sort	beta-lactam resistance response triggered by inactivation of a nonessential penicillin-binding protein.
publisher	Public Library of Science (PLoS)
publishDate	2009
url	https://doaj.org/article/883ebeaab7214dfd9cdd68b724abc5e4
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Beta-lactam resistance response triggered by inactivation of a nonessential penicillin-binding protein.

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