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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 β-lactamase AmpC from multiple Gra...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Microbiology
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5080387/ https://www.ncbi.nlm.nih.gov/pubmed/27795406 http://dx.doi.org/10.1128/mBio.01783-16 |
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author | Pérez-Gallego, Marcelo Torrens, Gabriel Castillo-Vera, Jane Moya, Bartolomé Zamorano, Laura Cabot, Gabriel Hultenby, Kjell Albertí, Sebastián Mellroth, Peter Henriques-Normark, Birgitta Normark, Staffan Oliver, Antonio Juan, Carlos |
author_facet | Pérez-Gallego, Marcelo Torrens, Gabriel Castillo-Vera, Jane Moya, Bartolomé Zamorano, Laura Cabot, Gabriel Hultenby, Kjell Albertí, Sebastián Mellroth, Peter Henriques-Normark, Birgitta Normark, Staffan Oliver, Antonio Juan, Carlos |
author_sort | Pérez-Gallego, Marcelo |
collection | PubMed |
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 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. |
format | Online Article Text |
id | pubmed-5080387 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | American Society for Microbiology |
record_format | MEDLINE/PubMed |
spelling | pubmed-50803872016-10-27 Impact of AmpC Derepression on Fitness and Virulence: the Mechanism or the Pathway? Pérez-Gallego, Marcelo Torrens, Gabriel Castillo-Vera, Jane Moya, Bartolomé Zamorano, Laura Cabot, Gabriel Hultenby, Kjell Albertí, Sebastián Mellroth, Peter Henriques-Normark, Birgitta Normark, Staffan Oliver, Antonio Juan, Carlos mBio Research Article 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. American Society for Microbiology 2016-10-25 /pmc/articles/PMC5080387/ /pubmed/27795406 http://dx.doi.org/10.1128/mBio.01783-16 Text en Copyright © 2016 Pérez-Gallego et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (http://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Article Pérez-Gallego, Marcelo Torrens, Gabriel Castillo-Vera, Jane Moya, Bartolomé Zamorano, Laura Cabot, Gabriel Hultenby, Kjell Albertí, Sebastián Mellroth, Peter Henriques-Normark, Birgitta Normark, Staffan Oliver, Antonio Juan, Carlos 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? |
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_short | 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? |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5080387/ https://www.ncbi.nlm.nih.gov/pubmed/27795406 http://dx.doi.org/10.1128/mBio.01783-16 |
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