Novel drug targets in cell wall biosynthesis exploited by gene disruption in Pseudomonas aeruginosa.

2.50
Hdl Handle:
http://hdl.handle.net/10033/621166
Title:
Novel drug targets in cell wall biosynthesis exploited by gene disruption in Pseudomonas aeruginosa.
Authors:
Elamin, Ayssar A; Steinicke, Susanne; Oehlmann, Wulf; Braun, Yvonne; Wanas, Hanaa; Shuralev, Eduard A; Huck, Carmen; Maringer, Marko; Rohde, Manfred ( 0000-0003-0522-3580 ) ; Singh, Mahavir
Abstract:
For clinicians, Pseudomonas aeruginosa is a nightmare pathogen that is one of the top three causes of opportunistic human infections. Therapy of P. aeruginosa infections is complicated due to its natural high intrinsic resistance to antibiotics. Active efflux and decreased uptake of drugs due to cell wall/membrane permeability appear to be important issues in the acquired antibiotic tolerance mechanisms. Bacterial cell wall biosynthesis enzymes have been shown to be essential for pathogenicity of Gram-negative bacteria. However, the role of these targets in virulence has not been identified in P. aeruginosa. Here, we report knockout (k.o) mutants of six cell wall biosynthesis targets (murA, PA4450; murD, PA4414; murF, PA4416; ppiB, PA1793; rmlA, PA5163; waaA, PA4988) in P. aeruginosa PAO1, and characterized these in order to find out whether these genes and their products contribute to pathogenicity and virulence of P. aeruginosa. Except waaA k.o, deletion of cell wall biosynthesis targets significantly reduced growth rate in minimal medium compared to the parent strain. The k.o mutants showed exciting changes in cell morphology and colonial architectures. Remarkably, ΔmurF cells became grossly enlarged. Moreover, the mutants were also attenuated in vivo in a mouse infection model except ΔmurF and ΔwaaA and proved to be more sensitive to macrophage-mediated killing than the wild-type strain. Interestingly, the deletion of the murA gene resulted in loss of virulence activity in mice, and the virulence was restored in a plant model by unknown mechanism. This study demonstrates that cell wall targets contribute significantly to intracellular survival, in vivo growth, and pathogenesis of P. aeruginosa. In conclusion, these findings establish a link between cell wall targets and virulence of P. aeruginosa and thus may lead to development of novel drugs for the treatment of P. aeruginosa infection.
Affiliation:
Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr.7, 38124 Braunschweig, Germany.
Citation:
Novel drug targets in cell wall biosynthesis exploited by gene disruption in Pseudomonas aeruginosa. 2017, 12 (10):e0186801 PLoS ONE
Journal:
PloS one
Issue Date:
2017
URI:
http://hdl.handle.net/10033/621166
DOI:
10.1371/journal.pone.0186801
PubMed ID:
29045498
Type:
Article
Language:
en
ISSN:
1932-6203
Appears in Collections:
publications of the central unit for microscopy (ZEIM)

Full metadata record

DC FieldValue Language
dc.contributor.authorElamin, Ayssar Aen
dc.contributor.authorSteinicke, Susanneen
dc.contributor.authorOehlmann, Wulfen
dc.contributor.authorBraun, Yvonneen
dc.contributor.authorWanas, Hanaaen
dc.contributor.authorShuralev, Eduard Aen
dc.contributor.authorHuck, Carmenen
dc.contributor.authorMaringer, Markoen
dc.contributor.authorRohde, Manfreden
dc.contributor.authorSingh, Mahaviren
dc.date.accessioned2017-11-07T14:05:03Z-
dc.date.available2017-11-07T14:05:03Z-
dc.date.issued2017-
dc.identifier.citationNovel drug targets in cell wall biosynthesis exploited by gene disruption in Pseudomonas aeruginosa. 2017, 12 (10):e0186801 PLoS ONEen
dc.identifier.issn1932-6203-
dc.identifier.pmid29045498-
dc.identifier.doi10.1371/journal.pone.0186801-
dc.identifier.urihttp://hdl.handle.net/10033/621166-
dc.description.abstractFor clinicians, Pseudomonas aeruginosa is a nightmare pathogen that is one of the top three causes of opportunistic human infections. Therapy of P. aeruginosa infections is complicated due to its natural high intrinsic resistance to antibiotics. Active efflux and decreased uptake of drugs due to cell wall/membrane permeability appear to be important issues in the acquired antibiotic tolerance mechanisms. Bacterial cell wall biosynthesis enzymes have been shown to be essential for pathogenicity of Gram-negative bacteria. However, the role of these targets in virulence has not been identified in P. aeruginosa. Here, we report knockout (k.o) mutants of six cell wall biosynthesis targets (murA, PA4450; murD, PA4414; murF, PA4416; ppiB, PA1793; rmlA, PA5163; waaA, PA4988) in P. aeruginosa PAO1, and characterized these in order to find out whether these genes and their products contribute to pathogenicity and virulence of P. aeruginosa. Except waaA k.o, deletion of cell wall biosynthesis targets significantly reduced growth rate in minimal medium compared to the parent strain. The k.o mutants showed exciting changes in cell morphology and colonial architectures. Remarkably, ΔmurF cells became grossly enlarged. Moreover, the mutants were also attenuated in vivo in a mouse infection model except ΔmurF and ΔwaaA and proved to be more sensitive to macrophage-mediated killing than the wild-type strain. Interestingly, the deletion of the murA gene resulted in loss of virulence activity in mice, and the virulence was restored in a plant model by unknown mechanism. This study demonstrates that cell wall targets contribute significantly to intracellular survival, in vivo growth, and pathogenesis of P. aeruginosa. In conclusion, these findings establish a link between cell wall targets and virulence of P. aeruginosa and thus may lead to development of novel drugs for the treatment of P. aeruginosa infection.en
dc.language.isoenen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.subject.meshAnimalsen
dc.subject.meshAnti-Bacterial Agentsen
dc.subject.meshBiosynthetic Pathwaysen
dc.subject.meshCell Wallen
dc.subject.meshColony Count, Microbialen
dc.subject.meshDNA, Bacterialen
dc.subject.meshExtracellular Spaceen
dc.subject.meshFemaleen
dc.subject.meshGene Knockdown Techniquesen
dc.subject.meshGenes, Bacterialen
dc.subject.meshGenetic Vectorsen
dc.subject.meshLettuceen
dc.subject.meshLipopolysaccharidesen
dc.subject.meshLungen
dc.subject.meshMacrophagesen
dc.subject.meshMiceen
dc.subject.meshModels, Biologicalen
dc.subject.meshMutationen
dc.subject.meshPeptidoglycanen
dc.subject.meshPlant Diseasesen
dc.subject.meshPseudomonas Infectionsen
dc.subject.meshPseudomonas aeruginosaen
dc.subject.meshRespiratory Tract Diseasesen
dc.subject.meshVirulenceen
dc.titleNovel drug targets in cell wall biosynthesis exploited by gene disruption in Pseudomonas aeruginosa.en
dc.typeArticleen
dc.contributor.departmentHelmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr.7, 38124 Braunschweig, Germany.en
dc.identifier.journalPloS oneen

Related articles on PubMed

This item is licensed under a Creative Commons License
Creative Commons
All Items in HZI are protected by copyright, with all rights reserved, unless otherwise indicated.