Peptidomimetic Antibiotics Target Outer-Membrane Biogenesis in Pseudomonas aeruginosa

被引：443

作者：

Srinivas, Nityakalyani ^{[2
]}

Jetter, Peter ^{[2
]}

Ueberbacher, Bernhard J. ^{[2
]}

Werneburg, Martina ^{[2
]}

Zerbe, Katja ^{[2
]}

Steinmann, Jessica ^{[2
]}

Van der Meijden, Benjamin ^{[2
]}

Bernardini, Francesca ^{[1
]}

Lederer, Alexander ^{[1
]}

Dias, Ricardo L. A. ^{[1
]}

Misson, Pauline E. ^{[1
]}

Henze, Heiko ^{[1
]}

Zumbrunn, Juerg ^{[1
]}

Gombert, Frank O. ^{[1
]}

Obrecht, Daniel ^{[1
]}

Hunziker, Peter ^{[3
]}

Schauer, Stefan ^{[3
]}

Ziegler, Urs ^{[4
]}

Kaech, Andres ^{[4
]}

Eberl, Leo ^{[5
]}

Riedel, Kathrin ^{[5
]}

DeMarco, Steven J. ^{[1
]}

Robinson, John A. ^{[2
]}

机构：

[1] Polyphor AG, CH-4123 Allschwil, Switzerland

[2] Univ Zurich, Dept Chem, CH-8057 Zurich, Switzerland

[3] Funct Genom Ctr Zurich, CH-8057 Zurich, Switzerland

[4] Univ Zurich, Ctr Microscopy & Image Anal, CH-8057 Zurich, Switzerland

[5] Univ Zurich, Dept Microbiol, CH-8057 Zurich, Switzerland

来源：

SCIENCE | 2010年 / 327卷 / 5968期

基金：

瑞士国家科学基金会;

关键词：

ANTIMICROBIAL PEPTIDE PROTEGRIN; SOLID-STATE NMR; CYSTIC-FIBROSIS AIRWAY; ESCHERICHIA-COLI; HAIRPIN MIMETICS; LIPID-BILAYERS; BROAD-SPECTRUM; LIPOPOLYSACCHARIDE; IDENTIFICATION; PERMEABILITY;

D O I：

10.1126/science.1182749

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 spp., but was largely inactive against other Gram-negative and Gram-positive bacteria. Biochemical and genetic studies showed that the peptidomimetics had a non-membrane-lytic mechanism of action and identified a homolog of the beta-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.

引用

页码：1010 / 1013

页数：4

共 30 条

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