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Involvement of hpap2 and dgkA Genes in Colistin Resistance Mediated by mcr Determinants
Plasmid-mediated colistin resistance (mcr) determinants are challenging the efficacy of polymyxins against Gram-negative pathogens. Among 10 mcr genes described so far, the major determinants mcr-1 and mcr-3 are found closely linked to hpap2 or dgkA genes, encoding a hypothetical phosphatidic acid p...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7559476/ https://www.ncbi.nlm.nih.gov/pubmed/32842668 http://dx.doi.org/10.3390/antibiotics9090531 |
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author | Gallardo, Alejandro Ugarte-Ruiz, María Hernández, Marta Miguela-Villoldo, Pedro Rodríguez-Lázaro, David Domínguez, Lucas Quesada, Alberto |
author_facet | Gallardo, Alejandro Ugarte-Ruiz, María Hernández, Marta Miguela-Villoldo, Pedro Rodríguez-Lázaro, David Domínguez, Lucas Quesada, Alberto |
author_sort | Gallardo, Alejandro |
collection | PubMed |
description | Plasmid-mediated colistin resistance (mcr) determinants are challenging the efficacy of polymyxins against Gram-negative pathogens. Among 10 mcr genes described so far, the major determinants mcr-1 and mcr-3 are found closely linked to hpap2 or dgkA genes, encoding a hypothetical phosphatidic acid phosphatase of type 2 (PAP2) and a diacylglycerol kinase, respectively, whose functions are still unknown. In this study, mcr-1, mcr-1–hpap2, mcr-3, and mcr-3–dgkA were expressed in Escherichia coli, and recombinant strains were analyzed to detect antimicrobial susceptibility and changes in the expression of genes involved in phospholipid metabolism. The mcr-1 or mcr-3 single genes were enough to drive growth on colistin selective media, although co-expression of linked genes conferred maximal antibiotic resistance. Expression of mcr determinants downregulated endogenous genes involved in lipopolysaccharide (LPS) modification or phospholipid recycling, although to different extents of repression: strong for arnB, ybjG, and pmrR; medium for eptA, lpxT, and dgkA; small for bacA and pgpB. Four of these genes (bacA, lpxT, pgpB, and ybjG) encode undecaprenyl pyrophosphate (UPP) phosphatases. In these conditions, cells presented resistance against bacitracin, an antibiotic that sequesters UPP from PAP2 enzymes. The hpap2 and dgkA genes might play a role in colistin resistance by compensating for phospholipid metabolism functions altered during LPS modification by colistin resistance determinants. |
format | Online Article Text |
id | pubmed-7559476 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-75594762020-10-26 Involvement of hpap2 and dgkA Genes in Colistin Resistance Mediated by mcr Determinants Gallardo, Alejandro Ugarte-Ruiz, María Hernández, Marta Miguela-Villoldo, Pedro Rodríguez-Lázaro, David Domínguez, Lucas Quesada, Alberto Antibiotics (Basel) Article Plasmid-mediated colistin resistance (mcr) determinants are challenging the efficacy of polymyxins against Gram-negative pathogens. Among 10 mcr genes described so far, the major determinants mcr-1 and mcr-3 are found closely linked to hpap2 or dgkA genes, encoding a hypothetical phosphatidic acid phosphatase of type 2 (PAP2) and a diacylglycerol kinase, respectively, whose functions are still unknown. In this study, mcr-1, mcr-1–hpap2, mcr-3, and mcr-3–dgkA were expressed in Escherichia coli, and recombinant strains were analyzed to detect antimicrobial susceptibility and changes in the expression of genes involved in phospholipid metabolism. The mcr-1 or mcr-3 single genes were enough to drive growth on colistin selective media, although co-expression of linked genes conferred maximal antibiotic resistance. Expression of mcr determinants downregulated endogenous genes involved in lipopolysaccharide (LPS) modification or phospholipid recycling, although to different extents of repression: strong for arnB, ybjG, and pmrR; medium for eptA, lpxT, and dgkA; small for bacA and pgpB. Four of these genes (bacA, lpxT, pgpB, and ybjG) encode undecaprenyl pyrophosphate (UPP) phosphatases. In these conditions, cells presented resistance against bacitracin, an antibiotic that sequesters UPP from PAP2 enzymes. The hpap2 and dgkA genes might play a role in colistin resistance by compensating for phospholipid metabolism functions altered during LPS modification by colistin resistance determinants. MDPI 2020-08-22 /pmc/articles/PMC7559476/ /pubmed/32842668 http://dx.doi.org/10.3390/antibiotics9090531 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Gallardo, Alejandro Ugarte-Ruiz, María Hernández, Marta Miguela-Villoldo, Pedro Rodríguez-Lázaro, David Domínguez, Lucas Quesada, Alberto Involvement of hpap2 and dgkA Genes in Colistin Resistance Mediated by mcr Determinants |
title | Involvement of hpap2 and dgkA Genes in Colistin Resistance Mediated by mcr Determinants |
title_full | Involvement of hpap2 and dgkA Genes in Colistin Resistance Mediated by mcr Determinants |
title_fullStr | Involvement of hpap2 and dgkA Genes in Colistin Resistance Mediated by mcr Determinants |
title_full_unstemmed | Involvement of hpap2 and dgkA Genes in Colistin Resistance Mediated by mcr Determinants |
title_short | Involvement of hpap2 and dgkA Genes in Colistin Resistance Mediated by mcr Determinants |
title_sort | involvement of hpap2 and dgka genes in colistin resistance mediated by mcr determinants |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7559476/ https://www.ncbi.nlm.nih.gov/pubmed/32842668 http://dx.doi.org/10.3390/antibiotics9090531 |
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