Regulation of AmpC-Driven β-Lactam Resistance in <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content>: Different Pathways, Different Signaling

ABSTRACT The hyperproduction of the chromosomal AmpC β-lactamase is the main mechanism driving β-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 sc...

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Autores principales:	Gabriel Torrens, Sara Belén Hernández, Juan Alfonso Ayala, Bartolome Moya, Carlos Juan, Felipe Cava, Antonio Oliver
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	AmpC β-lactamase Pseudomonas aeruginosa muropeptide peptidoglycan Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/f099b4421f5d48b49781ba0b96cb367e
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spelling	oai:doaj.org-article:f099b4421f5d48b49781ba0b96cb367e2021-12-02T18:15:44ZRegulation of AmpC-Driven β-Lactam Resistance in <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content>: Different Pathways, Different Signaling10.1128/mSystems.00524-192379-5077https://doaj.org/article/f099b4421f5d48b49781ba0b96cb367e2019-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSystems.00524-19https://doaj.org/toc/2379-5077ABSTRACT The hyperproduction of the chromosomal AmpC β-lactamase is the main mechanism driving β-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-N-acetylmuramyl-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 β-lactamase production, dominate over the repressor (UDP-N-acetylmuramyl-pentapeptide). This study represents a major step in understanding the foundations of AmpC-dependent β-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 β-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 β-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.Gabriel TorrensSara Belén HernándezJuan Alfonso AyalaBartolome MoyaCarlos JuanFelipe CavaAntonio OliverAmerican Society for MicrobiologyarticleAmpC β-lactamasePseudomonas aeruginosamuropeptidepeptidoglycanMicrobiologyQR1-502ENmSystems, Vol 4, Iss 6 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	AmpC β-lactamase Pseudomonas aeruginosa muropeptide peptidoglycan Microbiology QR1-502
spellingShingle	AmpC β-lactamase Pseudomonas aeruginosa muropeptide peptidoglycan Microbiology QR1-502 Gabriel Torrens Sara Belén Hernández Juan Alfonso Ayala Bartolome Moya Carlos Juan Felipe Cava Antonio Oliver Regulation of AmpC-Driven β-Lactam Resistance in <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content>: Different Pathways, Different Signaling
description	ABSTRACT The hyperproduction of the chromosomal AmpC β-lactamase is the main mechanism driving β-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-N-acetylmuramyl-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 β-lactamase production, dominate over the repressor (UDP-N-acetylmuramyl-pentapeptide). This study represents a major step in understanding the foundations of AmpC-dependent β-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 β-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 β-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.
format	article
author	Gabriel Torrens Sara Belén Hernández Juan Alfonso Ayala Bartolome Moya Carlos Juan Felipe Cava Antonio Oliver
author_facet	Gabriel Torrens Sara Belén Hernández Juan Alfonso Ayala Bartolome Moya Carlos Juan Felipe Cava Antonio Oliver
author_sort	Gabriel Torrens
title	Regulation of AmpC-Driven β-Lactam Resistance in <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content>: Different Pathways, Different Signaling
title_short	Regulation of AmpC-Driven β-Lactam Resistance in <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content>: Different Pathways, Different Signaling
title_full	Regulation of AmpC-Driven β-Lactam Resistance in <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content>: Different Pathways, Different Signaling
title_fullStr	Regulation of AmpC-Driven β-Lactam Resistance in <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content>: Different Pathways, Different Signaling
title_full_unstemmed	Regulation of AmpC-Driven β-Lactam Resistance in <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content>: Different Pathways, Different Signaling
title_sort	regulation of ampc-driven β-lactam resistance in <named-content content-type="genus-species">pseudomonas aeruginosa</named-content>: different pathways, different signaling
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/f099b4421f5d48b49781ba0b96cb367e
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Regulation of AmpC-Driven β-Lactam Resistance in <named-content content-type="genus-species">Pseudomonas aeruginosa</named-content>: Different Pathways, Different Signaling

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