Synergy between Active Efflux and Outer Membrane Diffusion Defines Rules of Antibiotic Permeation into Gram-Negative Bacteria

ABSTRACT Gram-negative bacteria are notoriously resistant to antibiotics, but the extent of the resistance varies broadly between species. We report that in significant human pathogens Acinetobacter baumannii, Pseudomonas aeruginosa, and Burkholderia spp., the differences in antibiotic resistance ar...

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Autores principales:	Ganesh Krishnamoorthy, Inga V. Leus, Jon W. Weeks, David Wolloscheck, Valentin V. Rybenkov, Helen I. Zgurskaya
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	Acinetobacter Burkholderia Pseudomonas aeruginosa antibiotic resistance multidrug efflux outer membrane Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/adc70a34bd7f4c4f8e081217787984d9
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spelling	oai:doaj.org-article:adc70a34bd7f4c4f8e081217787984d92021-11-15T15:51:51ZSynergy between Active Efflux and Outer Membrane Diffusion Defines Rules of Antibiotic Permeation into Gram-Negative Bacteria10.1128/mBio.01172-172150-7511https://doaj.org/article/adc70a34bd7f4c4f8e081217787984d92017-11-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01172-17https://doaj.org/toc/2150-7511ABSTRACT Gram-negative bacteria are notoriously resistant to antibiotics, but the extent of the resistance varies broadly between species. We report that in significant human pathogens Acinetobacter baumannii, Pseudomonas aeruginosa, and Burkholderia spp., the differences in antibiotic resistance are largely defined by their penetration into the cell. For all tested antibiotics, the intracellular penetration was determined by a synergistic relationship between active efflux and the permeability barrier. We found that the outer membrane (OM) and efflux pumps select compounds on the basis of distinct properties and together universally protect bacteria from structurally diverse antibiotics. On the basis of their interactions with the permeability barriers, antibiotics can be divided into four clusters that occupy defined physicochemical spaces. Our results suggest that rules of intracellular penetration are intrinsic to these clusters. The identified specificities in the permeability barriers should help in the designing of successful therapeutic strategies against antibiotic-resistant pathogens. IMPORTANCE Multidrug-resistant strains of Gram-negative pathogens rapidly spread in clinics. Significant efforts worldwide are currently directed to finding the rules of permeation of antibiotics across two membrane envelopes of these bacteria. This study created the tools for analysis of and identified the major differences in antibacterial activities that distinguish the permeability barriers of P. aeruginosa, A. baumannii, Burkholderia thailandensis, and B. cepacia. We conclude that synergy between active efflux and the outer membrane barrier universally protects Gram-negative bacteria from antibiotics. We also found that the diversity of antibiotics affected by active efflux and outer membrane barriers is broader than previously thought and that antibiotics cluster according to specific biological determinants such as the requirement of specific porins in the OM, targeting of the OM, or specific recognition by efflux pumps. No universal rules of antibiotic permeation into Gram-negative bacteria apparently exist. Our results suggest that antibiotic clusters are defined by specific rules of permeation and that further studies could lead to their discovery.Ganesh KrishnamoorthyInga V. LeusJon W. WeeksDavid WolloscheckValentin V. RybenkovHelen I. ZgurskayaAmerican Society for MicrobiologyarticleAcinetobacterBurkholderiaPseudomonas aeruginosaantibiotic resistancemultidrug effluxouter membraneMicrobiologyQR1-502ENmBio, Vol 8, Iss 5 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Acinetobacter Burkholderia Pseudomonas aeruginosa antibiotic resistance multidrug efflux outer membrane Microbiology QR1-502
spellingShingle	Acinetobacter Burkholderia Pseudomonas aeruginosa antibiotic resistance multidrug efflux outer membrane Microbiology QR1-502 Ganesh Krishnamoorthy Inga V. Leus Jon W. Weeks David Wolloscheck Valentin V. Rybenkov Helen I. Zgurskaya Synergy between Active Efflux and Outer Membrane Diffusion Defines Rules of Antibiotic Permeation into Gram-Negative Bacteria
description	ABSTRACT Gram-negative bacteria are notoriously resistant to antibiotics, but the extent of the resistance varies broadly between species. We report that in significant human pathogens Acinetobacter baumannii, Pseudomonas aeruginosa, and Burkholderia spp., the differences in antibiotic resistance are largely defined by their penetration into the cell. For all tested antibiotics, the intracellular penetration was determined by a synergistic relationship between active efflux and the permeability barrier. We found that the outer membrane (OM) and efflux pumps select compounds on the basis of distinct properties and together universally protect bacteria from structurally diverse antibiotics. On the basis of their interactions with the permeability barriers, antibiotics can be divided into four clusters that occupy defined physicochemical spaces. Our results suggest that rules of intracellular penetration are intrinsic to these clusters. The identified specificities in the permeability barriers should help in the designing of successful therapeutic strategies against antibiotic-resistant pathogens. IMPORTANCE Multidrug-resistant strains of Gram-negative pathogens rapidly spread in clinics. Significant efforts worldwide are currently directed to finding the rules of permeation of antibiotics across two membrane envelopes of these bacteria. This study created the tools for analysis of and identified the major differences in antibacterial activities that distinguish the permeability barriers of P. aeruginosa, A. baumannii, Burkholderia thailandensis, and B. cepacia. We conclude that synergy between active efflux and the outer membrane barrier universally protects Gram-negative bacteria from antibiotics. We also found that the diversity of antibiotics affected by active efflux and outer membrane barriers is broader than previously thought and that antibiotics cluster according to specific biological determinants such as the requirement of specific porins in the OM, targeting of the OM, or specific recognition by efflux pumps. No universal rules of antibiotic permeation into Gram-negative bacteria apparently exist. Our results suggest that antibiotic clusters are defined by specific rules of permeation and that further studies could lead to their discovery.
format	article
author	Ganesh Krishnamoorthy Inga V. Leus Jon W. Weeks David Wolloscheck Valentin V. Rybenkov Helen I. Zgurskaya
author_facet	Ganesh Krishnamoorthy Inga V. Leus Jon W. Weeks David Wolloscheck Valentin V. Rybenkov Helen I. Zgurskaya
author_sort	Ganesh Krishnamoorthy
title	Synergy between Active Efflux and Outer Membrane Diffusion Defines Rules of Antibiotic Permeation into Gram-Negative Bacteria
title_short	Synergy between Active Efflux and Outer Membrane Diffusion Defines Rules of Antibiotic Permeation into Gram-Negative Bacteria
title_full	Synergy between Active Efflux and Outer Membrane Diffusion Defines Rules of Antibiotic Permeation into Gram-Negative Bacteria
title_fullStr	Synergy between Active Efflux and Outer Membrane Diffusion Defines Rules of Antibiotic Permeation into Gram-Negative Bacteria
title_full_unstemmed	Synergy between Active Efflux and Outer Membrane Diffusion Defines Rules of Antibiotic Permeation into Gram-Negative Bacteria
title_sort	synergy between active efflux and outer membrane diffusion defines rules of antibiotic permeation into gram-negative bacteria
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/adc70a34bd7f4c4f8e081217787984d9
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Synergy between Active Efflux and Outer Membrane Diffusion Defines Rules of Antibiotic Permeation into Gram-Negative Bacteria

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