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

ABSTRACT 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 β-lactamase AmpC from mul...

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Autores principales:	Marcelo Pérez-Gallego, Gabriel Torrens, Jane Castillo-Vera, Bartolomé Moya, Laura Zamorano, Gabriel Cabot, Kjell Hultenby, Sebastián Albertí, Peter Mellroth, Birgitta Henriques-Normark, Staffan Normark, Antonio Oliver, Carlos Juan
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2016
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/d86072b1075643c8bccb8f8c41548818
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spelling	oai:doaj.org-article:d86072b1075643c8bccb8f8c415488182021-11-15T15:50:14ZImpact of AmpC Derepression on Fitness and Virulence: the Mechanism or the Pathway?10.1128/mBio.01783-162150-7511https://doaj.org/article/d86072b1075643c8bccb8f8c415488182016-11-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01783-16https://doaj.org/toc/2150-7511ABSTRACT 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 β-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 β-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 β-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 β-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 β-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.Marcelo Pérez-GallegoGabriel TorrensJane Castillo-VeraBartolomé MoyaLaura ZamoranoGabriel CabotKjell HultenbySebastián AlbertíPeter MellrothBirgitta Henriques-NormarkStaffan NormarkAntonio OliverCarlos JuanAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 7, Iss 5 (2016)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Marcelo Pérez-Gallego Gabriel Torrens Jane Castillo-Vera Bartolomé Moya Laura Zamorano Gabriel Cabot Kjell Hultenby Sebastián Albertí Peter Mellroth Birgitta Henriques-Normark Staffan Normark Antonio Oliver Carlos Juan Impact of AmpC Derepression on Fitness and Virulence: the Mechanism or the Pathway?
description	ABSTRACT 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 β-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 β-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 β-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 β-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 β-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.
format	article
author	Marcelo Pérez-Gallego Gabriel Torrens Jane Castillo-Vera Bartolomé Moya Laura Zamorano Gabriel Cabot Kjell Hultenby Sebastián Albertí Peter Mellroth Birgitta Henriques-Normark Staffan Normark Antonio Oliver Carlos Juan
author_facet	Marcelo Pérez-Gallego Gabriel Torrens Jane Castillo-Vera Bartolomé Moya Laura Zamorano Gabriel Cabot Kjell Hultenby Sebastián Albertí Peter Mellroth Birgitta Henriques-Normark Staffan Normark Antonio Oliver Carlos Juan
author_sort	Marcelo Pérez-Gallego
title	Impact of AmpC Derepression on Fitness and Virulence: the Mechanism or the Pathway?
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?
publisher	American Society for Microbiology
publishDate	2016
url	https://doaj.org/article/d86072b1075643c8bccb8f8c41548818
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Impact of AmpC Derepression on Fitness and Virulence: the Mechanism or the Pathway?

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