Regulation of AmpC-Driven beta-Lactam Resistance in Pseudomonas aeruginosa: Different Pathways, Different Signaling

The hyperproduction of the chromosomal AmpC beta-lactamase is the main mechanism driving beta-lactam resistance in Pseudomonas aeruginosa, one of the leading opportunistic pathogens causing nosocomial acute and chronic infections in patients with underlying respiratory diseases. In the current scena...

Descripción completa

Detalles Bibliográficos
Autores: Torrens, Gabriel, Hernandez, Sara Belen, Ayala, Juan Alfonso, Moya, Bartolome, Juan, Carlos, Cava, Felipe, Oliver, Antonio
Tipo de recurso: artículo
Fecha de publicación:2019
País:España
Institución:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/22647
Acceso en línea:https://hdl.handle.net/20.500.12105/22647
Access Level:acceso abierto
Palabra clave:AmpC beta-lactamase
Pseudomonas aeruginosa
muropeptide
peptidoglycan
id ES_3cfd00bf9e74e60d2d652e82ff6eedc5
oai_identifier_str oai:repisalud.isciii.es:20.500.12105/22647
network_acronym_str ES
network_name_str España
repository_id_str
spelling Regulation of AmpC-Driven beta-Lactam Resistance in Pseudomonas aeruginosa: Different Pathways, Different SignalingTorrens, GabrielHernandez, Sara BelenAyala, Juan AlfonsoMoya, BartolomeJuan, CarlosCava, FelipeOliver, AntonioAmpC beta-lactamasePseudomonas aeruginosamuropeptidepeptidoglycanThe hyperproduction of the chromosomal AmpC beta-lactamase is the main mechanism driving beta-lactam resistance in Pseudomonas aeruginosa, one of the leading opportunistic pathogens causing nosocomial acute and chronic infections in patients with underlying respiratory diseases. In the current scenario of the shortage of effective antipseudomonal drugs, understanding the molecular mechanisms mediating AmpC hyperproduction in order to develop new therapeutics against this fearsome pathogen is of great importance. It has been accepted for decades that certain cell wall-derived soluble fragments (muropeptides) modulate AmpC production by complexing with the transcriptional regulator AmpR and acquiring different conformations that activate/repress ampC expression. However, these peptidoglycan-derived signals have never been characterized in the highly prevalent P. aeruginosa stable AmpC hyperproducer mutants. Here, we demonstrate that the previously described fragments enabling the transient ampC hyperexpression during cefoxitin induction (1,6-anhydro-N-acetylmuramyl-pentapeptides) also underlie the dacB (penicillin binding protein 4 [PBP4]) mutation-driven stable hyperproduction but differ from the 1,6-anhydro-N-acetylmuramyl-tripeptides notably overaccumulated in the ampD knockout mutant. In addition, a simultaneous greater accumulation of both activators appears linked to higher levels of AmpC hyperproduction, although our results suggest a much stronger AmpC-activating potency for the 1,6-anhydro-Nacetylmuramyl-pentapeptide. Collectively, our results propose a model of AmpC control where the activator fragments, with qualitative and quantitative particularities depending on the pathways and levels of beta-lactamase production, dominate over the repressor (UDP-N-acetylmuramyl-pentapeptide). This study represents a major step in understanding the foundations of AmpC-dependent beta-lactam resistance in P. aeruginosa, potentially useful to open new therapeutic conceptions intended to interfere with the abovementioned cell wall-derived signaling. IMPORTANCE The extensive use of beta-lactam antibiotics and the bacterial adaptive capacity have led to the apparently unstoppable increase of antimicrobial resistance, one of the current major global health challenges. In the leading nosocomial pathogen Pseudomonas aeruginosa, the mutation-driven AmpC beta-lactamase hyperproduction stands out as the main resistance mechanism, but the molecular cues enabling this system have remained elusive until now. Here, we provide for the first time direct and quantitative information about the soluble cell wall-derived fragments accounting for the different levels and pathways of AmpC hyperproduction. Based on these results, we propose a hierarchical model of signals which ultimately govern ampC hyperexpression and resistance.American Society for Microbiology (ASM)20242024-09-1020192019-11-0120192019-11-01research articlehttp://purl.org/coar/resource_type/c_2df8fbb1info:eu-repo/semantics/articlehttps://hdl.handle.net/20.500.12105/22647reponame:Repisaludinstname:Instituto de Salud Carlos III (ISCIII)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:repisalud.isciii.es:20.500.12105/226472026-06-12T12:43:37Z
dc.title.none.fl_str_mv Regulation of AmpC-Driven beta-Lactam Resistance in Pseudomonas aeruginosa: Different Pathways, Different Signaling
title Regulation of AmpC-Driven beta-Lactam Resistance in Pseudomonas aeruginosa: Different Pathways, Different Signaling
spellingShingle Regulation of AmpC-Driven beta-Lactam Resistance in Pseudomonas aeruginosa: Different Pathways, Different Signaling
Torrens, Gabriel
AmpC beta-lactamase
Pseudomonas aeruginosa
muropeptide
peptidoglycan
title_short Regulation of AmpC-Driven beta-Lactam Resistance in Pseudomonas aeruginosa: Different Pathways, Different Signaling
title_full Regulation of AmpC-Driven beta-Lactam Resistance in Pseudomonas aeruginosa: Different Pathways, Different Signaling
title_fullStr Regulation of AmpC-Driven beta-Lactam Resistance in Pseudomonas aeruginosa: Different Pathways, Different Signaling
title_full_unstemmed Regulation of AmpC-Driven beta-Lactam Resistance in Pseudomonas aeruginosa: Different Pathways, Different Signaling
title_sort Regulation of AmpC-Driven beta-Lactam Resistance in Pseudomonas aeruginosa: Different Pathways, Different Signaling
dc.creator.none.fl_str_mv Torrens, Gabriel
Hernandez, Sara Belen
Ayala, Juan Alfonso
Moya, Bartolome
Juan, Carlos
Cava, Felipe
Oliver, Antonio
author Torrens, Gabriel
author_facet Torrens, Gabriel
Hernandez, Sara Belen
Ayala, Juan Alfonso
Moya, Bartolome
Juan, Carlos
Cava, Felipe
Oliver, Antonio
author_role author
author2 Hernandez, Sara Belen
Ayala, Juan Alfonso
Moya, Bartolome
Juan, Carlos
Cava, Felipe
Oliver, Antonio
author2_role author
author
author
author
author
author
dc.contributor.none.fl_str_mv
dc.subject.none.fl_str_mv AmpC beta-lactamase
Pseudomonas aeruginosa
muropeptide
peptidoglycan
topic AmpC beta-lactamase
Pseudomonas aeruginosa
muropeptide
peptidoglycan
description The hyperproduction of the chromosomal AmpC beta-lactamase is the main mechanism driving beta-lactam resistance in Pseudomonas aeruginosa, one of the leading opportunistic pathogens causing nosocomial acute and chronic infections in patients with underlying respiratory diseases. In the current scenario of the shortage of effective antipseudomonal drugs, understanding the molecular mechanisms mediating AmpC hyperproduction in order to develop new therapeutics against this fearsome pathogen is of great importance. It has been accepted for decades that certain cell wall-derived soluble fragments (muropeptides) modulate AmpC production by complexing with the transcriptional regulator AmpR and acquiring different conformations that activate/repress ampC expression. However, these peptidoglycan-derived signals have never been characterized in the highly prevalent P. aeruginosa stable AmpC hyperproducer mutants. Here, we demonstrate that the previously described fragments enabling the transient ampC hyperexpression during cefoxitin induction (1,6-anhydro-N-acetylmuramyl-pentapeptides) also underlie the dacB (penicillin binding protein 4 [PBP4]) mutation-driven stable hyperproduction but differ from the 1,6-anhydro-N-acetylmuramyl-tripeptides notably overaccumulated in the ampD knockout mutant. In addition, a simultaneous greater accumulation of both activators appears linked to higher levels of AmpC hyperproduction, although our results suggest a much stronger AmpC-activating potency for the 1,6-anhydro-Nacetylmuramyl-pentapeptide. Collectively, our results propose a model of AmpC control where the activator fragments, with qualitative and quantitative particularities depending on the pathways and levels of beta-lactamase production, dominate over the repressor (UDP-N-acetylmuramyl-pentapeptide). This study represents a major step in understanding the foundations of AmpC-dependent beta-lactam resistance in P. aeruginosa, potentially useful to open new therapeutic conceptions intended to interfere with the abovementioned cell wall-derived signaling. IMPORTANCE The extensive use of beta-lactam antibiotics and the bacterial adaptive capacity have led to the apparently unstoppable increase of antimicrobial resistance, one of the current major global health challenges. In the leading nosocomial pathogen Pseudomonas aeruginosa, the mutation-driven AmpC beta-lactamase hyperproduction stands out as the main resistance mechanism, but the molecular cues enabling this system have remained elusive until now. Here, we provide for the first time direct and quantitative information about the soluble cell wall-derived fragments accounting for the different levels and pathways of AmpC hyperproduction. Based on these results, we propose a hierarchical model of signals which ultimately govern ampC hyperexpression and resistance.
publishDate 2019
dc.date.none.fl_str_mv 2019
2019-11-01
2019
2019-11-01
2024
2024-09-10
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/20.500.12105/22647
url https://hdl.handle.net/20.500.12105/22647
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.publisher.none.fl_str_mv American Society for Microbiology (ASM)
publisher.none.fl_str_mv American Society for Microbiology (ASM)
dc.source.none.fl_str_mv reponame:Repisalud
instname:Instituto de Salud Carlos III (ISCIII)
instname_str Instituto de Salud Carlos III (ISCIII)
reponame_str Repisalud
collection Repisalud
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869406411427938304
score 15,811543

Similares en LA Referencia