Impact of AmpC Derepression on Fitness and Virulence: the Mechanism or the Pathway?

Understanding the interplay between antibiotic resistance and bacterial fitness and virulence is essential to guide individual treatments and improve global antibiotic policies. A paradigmatic example of a resistance mechanism is the intrinsic inducible chromosomal beta-lactamase AmpC from multiple...

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Autores: Pérez-Gallego, Marcelo, Torrens, Gabriel, Castillo-Vera, Jane, Moya, Bartolome, Zamorano, Laura, Cabot, Gabriel, Hultenby, Kjell, Alberti, Sebastian, Mellroth, Peter, Henriques-Normark, Birgitta, Normark, Staffan, Oliver, Antonio, Juan, Carlos
Tipo de recurso: artículo
Fecha de publicación:2016
País:España
Institución:Conselleria de Salut i Consum del Govern de les Illes Balears
Repositorio:Docusalut
Idioma:inglés
OAI Identifier:oai:docusalut.com:20.500.13003/10229
Acceso en línea:https://hdl.handle.net/20.500.13003/10229
Access Level:acceso abierto
Palabra clave:Virulence
beta-Lactamases
Gene Deletion
Peptidoglycan
Membrane Transport Proteins
Bacterial Proteins
Pseudomonas aeruginosa
Cell Wall
N-Acetylmuramoyl-L-alanine Amidase
beta-Lactamasas
Pared Celular
Virulencia
N-Acetil Muramoil-L-Alanina Amidasa
Peptidoglicano
Proteínas de Transporte de Membrana
Proteínas Bacterianas
Eliminación de Gen
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dc.title.none.fl_str_mv Impact of AmpC Derepression on Fitness and Virulence: the Mechanism or the Pathway?
title Impact of AmpC Derepression on Fitness and Virulence: the Mechanism or the Pathway?
spellingShingle Impact of AmpC Derepression on Fitness and Virulence: the Mechanism or the Pathway?
Pérez-Gallego, Marcelo
Virulence
beta-Lactamases
Gene Deletion
Peptidoglycan
Membrane Transport Proteins
Bacterial Proteins
Pseudomonas aeruginosa
Cell Wall
N-Acetylmuramoyl-L-alanine Amidase
beta-Lactamasas
Pared Celular
Virulencia
N-Acetil Muramoil-L-Alanina Amidasa
Peptidoglicano
Proteínas de Transporte de Membrana
Proteínas Bacterianas
Eliminación de Gen
Pseudomonas aeruginosa
title_short Impact of AmpC Derepression on Fitness and Virulence: the Mechanism or the Pathway?
title_full Impact of AmpC Derepression on Fitness and Virulence: the Mechanism or the Pathway?
title_fullStr Impact of AmpC Derepression on Fitness and Virulence: the Mechanism or the Pathway?
title_full_unstemmed Impact of AmpC Derepression on Fitness and Virulence: the Mechanism or the Pathway?
title_sort Impact of AmpC Derepression on Fitness and Virulence: the Mechanism or the Pathway?
dc.creator.none.fl_str_mv Pérez-Gallego, Marcelo
Torrens, Gabriel
Castillo-Vera, Jane
Moya, Bartolome
Zamorano, Laura
Cabot, Gabriel
Hultenby, Kjell
Alberti, Sebastian
Mellroth, Peter
Henriques-Normark, Birgitta
Normark, Staffan
Oliver, Antonio
Juan, Carlos
author Pérez-Gallego, Marcelo
author_facet Pérez-Gallego, Marcelo
Torrens, Gabriel
Castillo-Vera, Jane
Moya, Bartolome
Zamorano, Laura
Cabot, Gabriel
Hultenby, Kjell
Alberti, Sebastian
Mellroth, Peter
Henriques-Normark, Birgitta
Normark, Staffan
Oliver, Antonio
Juan, Carlos
author_role author
author2 Torrens, Gabriel
Castillo-Vera, Jane
Moya, Bartolome
Zamorano, Laura
Cabot, Gabriel
Hultenby, Kjell
Alberti, Sebastian
Mellroth, Peter
Henriques-Normark, Birgitta
Normark, Staffan
Oliver, Antonio
Juan, Carlos
author2_role author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv
dc.subject.none.fl_str_mv Virulence
beta-Lactamases
Gene Deletion
Peptidoglycan
Membrane Transport Proteins
Bacterial Proteins
Pseudomonas aeruginosa
Cell Wall
N-Acetylmuramoyl-L-alanine Amidase
beta-Lactamasas
Pared Celular
Virulencia
N-Acetil Muramoil-L-Alanina Amidasa
Peptidoglicano
Proteínas de Transporte de Membrana
Proteínas Bacterianas
Eliminación de Gen
Pseudomonas aeruginosa
topic Virulence
beta-Lactamases
Gene Deletion
Peptidoglycan
Membrane Transport Proteins
Bacterial Proteins
Pseudomonas aeruginosa
Cell Wall
N-Acetylmuramoyl-L-alanine Amidase
beta-Lactamasas
Pared Celular
Virulencia
N-Acetil Muramoil-L-Alanina Amidasa
Peptidoglicano
Proteínas de Transporte de Membrana
Proteínas Bacterianas
Eliminación de Gen
Pseudomonas aeruginosa
description Understanding the interplay between antibiotic resistance and bacterial fitness and virulence is essential to guide individual treatments and improve global antibiotic policies. A paradigmatic example of a resistance mechanism is the intrinsic inducible chromosomal beta-lactamase AmpC from multiple Gram-negative bacteria, including Pseudomonas aeruginosa, a major nosocomial pathogen. The regulation of ampC expression is intimately linked to peptidoglycan recycling, and AmpC-mediated beta-lactam resistance is frequently mediated by inactivating mutations in ampD, encoding an N-acetyl-anhydromuramyl-L-alanine amidase, affecting the levels of ampC-activating muropeptides. Here we dissect the impact of the multiple pathways causing AmpC hyperproduction on P. aeruginosa fitness and virulence. Through a detailed analysis, we demonstrate that the lack of all three P. aeruginosa AmpD amidases causes a dramatic effect in fitness and pathogenicity, severely compromising growth rates, motility, and cytotoxicity; the latter effect is likely achieved by repressing key virulence factors, such as protease LasA, phospholipase C, or type III secretion system components. We also show that ampC overexpression is required but not sufficient to confer the growth-motility-cytotoxicity impaired phenotype and that alternative pathways leading to similar levels of ampC hyperexpression and resistance, such as those involving PBP4, had no fitness-virulence cost. Further analysis indicated that fitness-virulence impairment is caused by overexpressing ampC in the absence of cell wall recycling, as reproduced by expressing ampC from a plasmid in an AmpG (muropeptide permease)-deficient background. Thus, our findings represent a major step in the understanding of beta-lactam resistance biology and its interplay with fitness and pathogenesis. IMPORTANCE Understanding the impact of antibiotic resistance mechanisms on bacterial pathogenesis is critical to curb the spread of antibiotic resistance. A particularly noteworthy antibiotic resistance mechanism is the beta-lactamase AmpC, produced by Pseudomonas aeruginosa, a major pathogen causing hospital-acquired infections. The regulation of AmpC is linked to the cell wall recycling pathways, and frequently, resistance to beta-lactams is caused by mutation of several of the components of the cell wall recycling pathways such as AmpD. Here we dissect the impact of the pathways for AmpC hyperproduction on virulence, showing that the lack of all three P. aeruginosa AmpD amidases causes a major effect in fitness and pathogenicity, compromising growth, motility, and cytotoxicity. Further analysis indicated that fitness-virulence impairment is specifically caused by the hyperproduction of AmpC in the absence of cell wall recycling. Our work provides valuable information for delineating future strategies for combating P. aeruginosa infections by simultaneously targeting virulence and antibiotic resistance.
publishDate 2016
dc.date.none.fl_str_mv 2016
2016-09-01
2016
2016-09-01
dc.type.none.fl_str_mv research article
http://purl.org/coar/resource_type/c_2df8fbb1
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://hdl.handle.net/20.500.13003/10229
url https://hdl.handle.net/20.500.13003/10229
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Amer Soc Microbiology
publisher.none.fl_str_mv Amer Soc Microbiology
dc.source.none.fl_str_mv reponame:Docusalut
instname:Conselleria de Salut i Consum del Govern de les Illes Balears
instname_str Conselleria de Salut i Consum del Govern de les Illes Balears
reponame_str Docusalut
collection Docusalut
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869421681607442432
spelling Impact of AmpC Derepression on Fitness and Virulence: the Mechanism or the Pathway?Pérez-Gallego, MarceloTorrens, GabrielCastillo-Vera, JaneMoya, BartolomeZamorano, LauraCabot, GabrielHultenby, KjellAlberti, SebastianMellroth, PeterHenriques-Normark, BirgittaNormark, StaffanOliver, AntonioJuan, CarlosVirulencebeta-LactamasesGene DeletionPeptidoglycanMembrane Transport ProteinsBacterial ProteinsPseudomonas aeruginosaCell WallN-Acetylmuramoyl-L-alanine Amidasebeta-LactamasasPared CelularVirulenciaN-Acetil Muramoil-L-Alanina AmidasaPeptidoglicanoProteínas de Transporte de MembranaProteínas BacterianasEliminación de GenPseudomonas aeruginosaUnderstanding the interplay between antibiotic resistance and bacterial fitness and virulence is essential to guide individual treatments and improve global antibiotic policies. A paradigmatic example of a resistance mechanism is the intrinsic inducible chromosomal beta-lactamase AmpC from multiple Gram-negative bacteria, including Pseudomonas aeruginosa, a major nosocomial pathogen. The regulation of ampC expression is intimately linked to peptidoglycan recycling, and AmpC-mediated beta-lactam resistance is frequently mediated by inactivating mutations in ampD, encoding an N-acetyl-anhydromuramyl-L-alanine amidase, affecting the levels of ampC-activating muropeptides. Here we dissect the impact of the multiple pathways causing AmpC hyperproduction on P. aeruginosa fitness and virulence. Through a detailed analysis, we demonstrate that the lack of all three P. aeruginosa AmpD amidases causes a dramatic effect in fitness and pathogenicity, severely compromising growth rates, motility, and cytotoxicity; the latter effect is likely achieved by repressing key virulence factors, such as protease LasA, phospholipase C, or type III secretion system components. We also show that ampC overexpression is required but not sufficient to confer the growth-motility-cytotoxicity impaired phenotype and that alternative pathways leading to similar levels of ampC hyperexpression and resistance, such as those involving PBP4, had no fitness-virulence cost. Further analysis indicated that fitness-virulence impairment is caused by overexpressing ampC in the absence of cell wall recycling, as reproduced by expressing ampC from a plasmid in an AmpG (muropeptide permease)-deficient background. Thus, our findings represent a major step in the understanding of beta-lactam resistance biology and its interplay with fitness and pathogenesis. IMPORTANCE Understanding the impact of antibiotic resistance mechanisms on bacterial pathogenesis is critical to curb the spread of antibiotic resistance. A particularly noteworthy antibiotic resistance mechanism is the beta-lactamase AmpC, produced by Pseudomonas aeruginosa, a major pathogen causing hospital-acquired infections. The regulation of AmpC is linked to the cell wall recycling pathways, and frequently, resistance to beta-lactams is caused by mutation of several of the components of the cell wall recycling pathways such as AmpD. Here we dissect the impact of the pathways for AmpC hyperproduction on virulence, showing that the lack of all three P. aeruginosa AmpD amidases causes a major effect in fitness and pathogenicity, compromising growth, motility, and cytotoxicity. Further analysis indicated that fitness-virulence impairment is specifically caused by the hyperproduction of AmpC in the absence of cell wall recycling. Our work provides valuable information for delineating future strategies for combating P. aeruginosa infections by simultaneously targeting virulence and antibiotic resistance.Amer Soc Microbiology20162016-09-0120162016-09-01research articlehttp://purl.org/coar/resource_type/c_2df8fbb1info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/20.500.13003/10229reponame:Docusalutinstname:Conselleria de Salut i Consum del Govern de les Illes BalearsInglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:docusalut.com:20.500.13003/102292026-06-22T12:44:07Z
score 15.81155

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