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Peptidomimetic antibiotics target outer membrane biogenesis in Pseudomonas aeruginosa


Srinivas, N; Jetter, P; Ueberbacher, B J; Werneburg, M; Zerbe, K; Steinmann, J; VanderMeijden, B; Bernardini, F; Lederer, A; Dias, R L A; Misson, P E; Henze, H; Zumbrunn, J; Gombert, F O; Obrecht, D; Hunziker, P; Schauer, S; Ziegler, U; Käch, A; Eberl, L; Riedel, K; DeMarco, S J; Robinson, J A (2010). Peptidomimetic antibiotics target outer membrane biogenesis in Pseudomonas aeruginosa. Science, 327(5968):1010-1013.

Abstract

Antibiotics with new mechanisms of action are urgently required to combat the growing health
threat posed by resistant pathogenic microorganisms. We synthesized a family of peptidomimetic
antibiotics, based on the antimicrobial peptide protegrin I. Several rounds of optimization gave a
lead compound that was active in the nanomolar range against gram-negative Pseudomonas sp.,
but was largely inactive against other Gram-negative and Gram-positive bacteria. Biochemical
and genetic studies showed the peptidomimetics had a non-membrane-lytic mechanism of action
and identified a homologue of the ß-barrel protein LptD (Imp/OstA), which functions in outer
membrane biogenesis, as a cellular target. The peptidomimetic showed potent antimicrobial
activity in a mouse septicemia infection model. Drug-resistant strains of Pseudomonas are a
serious health problem, so this family of antibiotics may have important therapeutic applications.

Abstract

Antibiotics with new mechanisms of action are urgently required to combat the growing health
threat posed by resistant pathogenic microorganisms. We synthesized a family of peptidomimetic
antibiotics, based on the antimicrobial peptide protegrin I. Several rounds of optimization gave a
lead compound that was active in the nanomolar range against gram-negative Pseudomonas sp.,
but was largely inactive against other Gram-negative and Gram-positive bacteria. Biochemical
and genetic studies showed the peptidomimetics had a non-membrane-lytic mechanism of action
and identified a homologue of the ß-barrel protein LptD (Imp/OstA), which functions in outer
membrane biogenesis, as a cellular target. The peptidomimetic showed potent antimicrobial
activity in a mouse septicemia infection model. Drug-resistant strains of Pseudomonas are a
serious health problem, so this family of antibiotics may have important therapeutic applications.

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Contributors:Organic Chemistry, Polyphor AG, Functional Genomics Center, Center for Microscopy, Micribiology Dept.
Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Center for Microscopy and Image Analysis
04 Faculty of Medicine > Functional Genomics Center Zurich
07 Faculty of Science > Department of Plant and Microbial Biology
08 University Research Priority Programs > Systems Biology / Functional Genomics
07 Faculty of Science > Department of Chemistry
Dewey Decimal Classification:570 Life sciences; biology
580 Plants (Botany)
610 Medicine & health
540 Chemistry
Language:English
Date:19 February 2010
Deposited On:26 Mar 2010 15:38
Last Modified:18 Apr 2018 11:40
Publisher:American Association for the Advancement of Science (AAAS)
ISSN:0036-8075
Funders:Swiss National Science Foundation, Commission for Technology and Innovation (CTI/KTI), EU 7th Framework Program
Additional Information:This is the author's version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution. The definitive version was published in Science Vol. 327. no. 5968, pp. 1010 - 1013; DOI: 10.1126/science.1182749
OA Status:Green
Free access at:Official URL. An embargo period may apply.
Publisher DOI:https://doi.org/10.1126/science.1182749
Official URL:http://www.sciencemag.org/cgi/content/full/327/5968/1010
PubMed ID:20167788
Project Information:
  • : FunderSNSF
  • : Grant ID
  • : Project TitleSwiss National Science Foundation
  • : Funder
  • : Grant ID
  • : Project TitleCommission for Technology and Innovation (CTI/KTI)
  • : Funder
  • : Grant ID
  • : Project TitleEU 7th Framework Program

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