Global Trends in Proteome Remodeling of the Outer Membrane Modulate Antimicrobial Permeability in <named-content content-type="genus-species">Klebsiella pneumoniae</named-content>

ABSTRACT In Gram-negative bacteria, the permeability of the outer membrane governs rates of antibiotic uptake and thus the efficacy of antimicrobial treatment. Hydrophilic drugs like β-lactam antibiotics depend on diffusion through pore-forming outer membrane proteins to reach their intracellular ta...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Andrea Rocker, Jake A. Lacey, Matthew J. Belousoff, Jonathan J. Wilksch, Richard A. Strugnell, Mark R. Davies, Trevor Lithgow
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	antimicrobial resistance porin OmpK37 beta-barrel carbapenem carbapenems Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/247288d710f642659e2235f566ef4e3c
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:247288d710f642659e2235f566ef4e3c
record_format	dspace
spelling	oai:doaj.org-article:247288d710f642659e2235f566ef4e3c2021-11-15T15:57:02ZGlobal Trends in Proteome Remodeling of the Outer Membrane Modulate Antimicrobial Permeability in <named-content content-type="genus-species">Klebsiella pneumoniae</named-content>10.1128/mBio.00603-202150-7511https://doaj.org/article/247288d710f642659e2235f566ef4e3c2020-04-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00603-20https://doaj.org/toc/2150-7511ABSTRACT In Gram-negative bacteria, the permeability of the outer membrane governs rates of antibiotic uptake and thus the efficacy of antimicrobial treatment. Hydrophilic drugs like β-lactam antibiotics depend on diffusion through pore-forming outer membrane proteins to reach their intracellular targets. In this study, we investigated the distribution of porin genes in more than 2,700 Klebsiella isolates and found a widespread loss of OmpK35 functionality, particularly in those strains isolated from clinical environments. Using a defined set of outer-membrane-remodeled mutants, the major porin OmpK35 was shown to be largely responsible for β-lactam permeation. Sequence similarity network analysis characterized the porin protein subfamilies and led to discovery of a new porin family member, OmpK38. Structure-based comparisons of OmpK35, OmpK36, OmpK37, OmpK38, and PhoE showed near-identical pore frameworks but defining differences in the sequence characteristics of the extracellular loops. Antibiotic sensitivity profiles of isogenic Klebsiella pneumoniae strains, each expressing a different porin as its dominant pore, revealed striking differences in the antibiotic permeability characteristics of each channel in a physiological context. Since K. pneumoniae is a nosocomial pathogen with high rates of antimicrobial resistance and concurrent mortality, these experiments elucidate the role of porins in conferring specific drug-resistant phenotypes in a global context, informing future research to combat antimicrobial resistance in K. pneumoniae. IMPORTANCE Klebsiella pneumoniae is a pathogen of humans with high rates of mortality and a recognized global rise in incidence of carbapenem-resistant K. pneumoniae (CRKP). The outer membrane of K. pneumoniae forms a permeability barrier that modulates the ability of antibiotics to reach their intracellular target. OmpK35, OmpK36, OmpK37, OmpK38, PhoE, and OmpK26 are porins in the outer membrane of K. pneumoniae, demonstrated here to have a causative relationship to drug resistance phenotypes in a physiological context. The data highlight that currently trialed combination treatments with a carbapenem and β-lactamase inhibitors could be effective on porin-deficient K. pneumoniae. Together with structural data, the results reveal the role of outer membrane proteome remodeling in antimicrobial resistance of K. pneumoniae and point to the role of extracellular loops, not channel parameters, in drug permeation. This significant finding warrants care in the development of phage therapies for K. pneumoniae infections, given the way porin expression will be modulated to confer phage-resistant—and collateral drug-resistant—phenotypes in K. pneumoniae.Andrea RockerJake A. LaceyMatthew J. BelousoffJonathan J. WilkschRichard A. StrugnellMark R. DaviesTrevor LithgowAmerican Society for Microbiologyarticleantimicrobial resistanceporinOmpK37beta-barrelcarbapenemcarbapenemsMicrobiologyQR1-502ENmBio, Vol 11, Iss 2 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	antimicrobial resistance porin OmpK37 beta-barrel carbapenem carbapenems Microbiology QR1-502
spellingShingle	antimicrobial resistance porin OmpK37 beta-barrel carbapenem carbapenems Microbiology QR1-502 Andrea Rocker Jake A. Lacey Matthew J. Belousoff Jonathan J. Wilksch Richard A. Strugnell Mark R. Davies Trevor Lithgow Global Trends in Proteome Remodeling of the Outer Membrane Modulate Antimicrobial Permeability in <named-content content-type="genus-species">Klebsiella pneumoniae</named-content>
description	ABSTRACT In Gram-negative bacteria, the permeability of the outer membrane governs rates of antibiotic uptake and thus the efficacy of antimicrobial treatment. Hydrophilic drugs like β-lactam antibiotics depend on diffusion through pore-forming outer membrane proteins to reach their intracellular targets. In this study, we investigated the distribution of porin genes in more than 2,700 Klebsiella isolates and found a widespread loss of OmpK35 functionality, particularly in those strains isolated from clinical environments. Using a defined set of outer-membrane-remodeled mutants, the major porin OmpK35 was shown to be largely responsible for β-lactam permeation. Sequence similarity network analysis characterized the porin protein subfamilies and led to discovery of a new porin family member, OmpK38. Structure-based comparisons of OmpK35, OmpK36, OmpK37, OmpK38, and PhoE showed near-identical pore frameworks but defining differences in the sequence characteristics of the extracellular loops. Antibiotic sensitivity profiles of isogenic Klebsiella pneumoniae strains, each expressing a different porin as its dominant pore, revealed striking differences in the antibiotic permeability characteristics of each channel in a physiological context. Since K. pneumoniae is a nosocomial pathogen with high rates of antimicrobial resistance and concurrent mortality, these experiments elucidate the role of porins in conferring specific drug-resistant phenotypes in a global context, informing future research to combat antimicrobial resistance in K. pneumoniae. IMPORTANCE Klebsiella pneumoniae is a pathogen of humans with high rates of mortality and a recognized global rise in incidence of carbapenem-resistant K. pneumoniae (CRKP). The outer membrane of K. pneumoniae forms a permeability barrier that modulates the ability of antibiotics to reach their intracellular target. OmpK35, OmpK36, OmpK37, OmpK38, PhoE, and OmpK26 are porins in the outer membrane of K. pneumoniae, demonstrated here to have a causative relationship to drug resistance phenotypes in a physiological context. The data highlight that currently trialed combination treatments with a carbapenem and β-lactamase inhibitors could be effective on porin-deficient K. pneumoniae. Together with structural data, the results reveal the role of outer membrane proteome remodeling in antimicrobial resistance of K. pneumoniae and point to the role of extracellular loops, not channel parameters, in drug permeation. This significant finding warrants care in the development of phage therapies for K. pneumoniae infections, given the way porin expression will be modulated to confer phage-resistant—and collateral drug-resistant—phenotypes in K. pneumoniae.
format	article
author	Andrea Rocker Jake A. Lacey Matthew J. Belousoff Jonathan J. Wilksch Richard A. Strugnell Mark R. Davies Trevor Lithgow
author_facet	Andrea Rocker Jake A. Lacey Matthew J. Belousoff Jonathan J. Wilksch Richard A. Strugnell Mark R. Davies Trevor Lithgow
author_sort	Andrea Rocker
title	Global Trends in Proteome Remodeling of the Outer Membrane Modulate Antimicrobial Permeability in <named-content content-type="genus-species">Klebsiella pneumoniae</named-content>
title_short	Global Trends in Proteome Remodeling of the Outer Membrane Modulate Antimicrobial Permeability in <named-content content-type="genus-species">Klebsiella pneumoniae</named-content>
title_full	Global Trends in Proteome Remodeling of the Outer Membrane Modulate Antimicrobial Permeability in <named-content content-type="genus-species">Klebsiella pneumoniae</named-content>
title_fullStr	Global Trends in Proteome Remodeling of the Outer Membrane Modulate Antimicrobial Permeability in <named-content content-type="genus-species">Klebsiella pneumoniae</named-content>
title_full_unstemmed	Global Trends in Proteome Remodeling of the Outer Membrane Modulate Antimicrobial Permeability in <named-content content-type="genus-species">Klebsiella pneumoniae</named-content>
title_sort	global trends in proteome remodeling of the outer membrane modulate antimicrobial permeability in <named-content content-type="genus-species">klebsiella pneumoniae</named-content>
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/247288d710f642659e2235f566ef4e3c
work_keys_str_mv	AT andrearocker globaltrendsinproteomeremodelingoftheoutermembranemodulateantimicrobialpermeabilityinnamedcontentcontenttypegenusspeciesklebsiellapneumoniaenamedcontent AT jakealacey globaltrendsinproteomeremodelingoftheoutermembranemodulateantimicrobialpermeabilityinnamedcontentcontenttypegenusspeciesklebsiellapneumoniaenamedcontent AT matthewjbelousoff globaltrendsinproteomeremodelingoftheoutermembranemodulateantimicrobialpermeabilityinnamedcontentcontenttypegenusspeciesklebsiellapneumoniaenamedcontent AT jonathanjwilksch globaltrendsinproteomeremodelingoftheoutermembranemodulateantimicrobialpermeabilityinnamedcontentcontenttypegenusspeciesklebsiellapneumoniaenamedcontent AT richardastrugnell globaltrendsinproteomeremodelingoftheoutermembranemodulateantimicrobialpermeabilityinnamedcontentcontenttypegenusspeciesklebsiellapneumoniaenamedcontent AT markrdavies globaltrendsinproteomeremodelingoftheoutermembranemodulateantimicrobialpermeabilityinnamedcontentcontenttypegenusspeciesklebsiellapneumoniaenamedcontent AT trevorlithgow globaltrendsinproteomeremodelingoftheoutermembranemodulateantimicrobialpermeabilityinnamedcontentcontenttypegenusspeciesklebsiellapneumoniaenamedcontent
_version_	1718427018429726720

Global Trends in Proteome Remodeling of the Outer Membrane Modulate Antimicrobial Permeability in <named-content content-type="genus-species">Klebsiella pneumoniae</named-content>

Ejemplares similares