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Muramyl Endopeptidase Spr Contributes to Intrinsic Vancomycin Resistance in Salmonella enterica Serovar Typhimurium

The impermeability barrier provided by the outer membrane of enteric bacteria, a feature lacking in Gram-positive bacteria, plays a major role in maintaining resistance to numerous antimicrobial compounds and antibiotics. Here we demonstrate that mutational inactivation of spr, coding for a muramyl...

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Autores principales: Vestö, Kim, Huseby, Douglas L., Snygg, Iina, Wang, Helen, Hughes, Diarmaid, Rhen, Mikael
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6301998/
https://www.ncbi.nlm.nih.gov/pubmed/30619108
http://dx.doi.org/10.3389/fmicb.2018.02941
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author Vestö, Kim
Huseby, Douglas L.
Snygg, Iina
Wang, Helen
Hughes, Diarmaid
Rhen, Mikael
author_facet Vestö, Kim
Huseby, Douglas L.
Snygg, Iina
Wang, Helen
Hughes, Diarmaid
Rhen, Mikael
author_sort Vestö, Kim
collection PubMed
description The impermeability barrier provided by the outer membrane of enteric bacteria, a feature lacking in Gram-positive bacteria, plays a major role in maintaining resistance to numerous antimicrobial compounds and antibiotics. Here we demonstrate that mutational inactivation of spr, coding for a muramyl endopeptidase, significantly sensitizes Salmonella enterica serovar Typhimurium to vancomycin without any accompanying apparent growth defect or outer membrane destabilization. A similar phenotype was not achieved by deleting the genes coding for muramyl endopeptidases MepA, PbpG, NlpC, YedA, or YhdO. The spr mutant showed increased autolytic behavior in response to not only vancomycin, but also to penicillin G, an antibiotic for which the mutant displayed a wild-type MIC. A screen for suppressor mutations of the spr mutant phenotype revealed that deletion of tsp (prc), encoding a periplasmic carboxypeptidase involved in processing Spr and PBP3, restored intrinsic resistance to vancomycin and reversed the autolytic phenotype of the spr mutant. Our data suggest that Spr contributes to intrinsic antibiotic resistance in S. Typhimurium without directly affecting the outer membrane permeability barrier. Furthermore, our data suggests that compounds targeting specific cell wall endopeptidases might have the potential to expand the activity spectrum of traditional Gram-positive antibiotics.
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spelling pubmed-63019982019-01-07 Muramyl Endopeptidase Spr Contributes to Intrinsic Vancomycin Resistance in Salmonella enterica Serovar Typhimurium Vestö, Kim Huseby, Douglas L. Snygg, Iina Wang, Helen Hughes, Diarmaid Rhen, Mikael Front Microbiol Microbiology The impermeability barrier provided by the outer membrane of enteric bacteria, a feature lacking in Gram-positive bacteria, plays a major role in maintaining resistance to numerous antimicrobial compounds and antibiotics. Here we demonstrate that mutational inactivation of spr, coding for a muramyl endopeptidase, significantly sensitizes Salmonella enterica serovar Typhimurium to vancomycin without any accompanying apparent growth defect or outer membrane destabilization. A similar phenotype was not achieved by deleting the genes coding for muramyl endopeptidases MepA, PbpG, NlpC, YedA, or YhdO. The spr mutant showed increased autolytic behavior in response to not only vancomycin, but also to penicillin G, an antibiotic for which the mutant displayed a wild-type MIC. A screen for suppressor mutations of the spr mutant phenotype revealed that deletion of tsp (prc), encoding a periplasmic carboxypeptidase involved in processing Spr and PBP3, restored intrinsic resistance to vancomycin and reversed the autolytic phenotype of the spr mutant. Our data suggest that Spr contributes to intrinsic antibiotic resistance in S. Typhimurium without directly affecting the outer membrane permeability barrier. Furthermore, our data suggests that compounds targeting specific cell wall endopeptidases might have the potential to expand the activity spectrum of traditional Gram-positive antibiotics. Frontiers Media S.A. 2018-12-14 /pmc/articles/PMC6301998/ /pubmed/30619108 http://dx.doi.org/10.3389/fmicb.2018.02941 Text en Copyright © 2018 Vestö, Huseby, Snygg, Wang, Hughes and Rhen. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Microbiology
Vestö, Kim
Huseby, Douglas L.
Snygg, Iina
Wang, Helen
Hughes, Diarmaid
Rhen, Mikael
Muramyl Endopeptidase Spr Contributes to Intrinsic Vancomycin Resistance in Salmonella enterica Serovar Typhimurium
title Muramyl Endopeptidase Spr Contributes to Intrinsic Vancomycin Resistance in Salmonella enterica Serovar Typhimurium
title_full Muramyl Endopeptidase Spr Contributes to Intrinsic Vancomycin Resistance in Salmonella enterica Serovar Typhimurium
title_fullStr Muramyl Endopeptidase Spr Contributes to Intrinsic Vancomycin Resistance in Salmonella enterica Serovar Typhimurium
title_full_unstemmed Muramyl Endopeptidase Spr Contributes to Intrinsic Vancomycin Resistance in Salmonella enterica Serovar Typhimurium
title_short Muramyl Endopeptidase Spr Contributes to Intrinsic Vancomycin Resistance in Salmonella enterica Serovar Typhimurium
title_sort muramyl endopeptidase spr contributes to intrinsic vancomycin resistance in salmonella enterica serovar typhimurium
topic Microbiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6301998/
https://www.ncbi.nlm.nih.gov/pubmed/30619108
http://dx.doi.org/10.3389/fmicb.2018.02941
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