Peptidomimetic antibiotics target outer-membrane biogenesis in Pseudomonas aeruginosa.

Nityakalyani Srinivas, Peter Jetter, Bernhard J Ueberbacher, Martina Werneburg, Katja Zerbe, Jessica Steinmann, Benjamin Van der Meijden, Francesca Bernardini, Alexander Lederer, Ricardo L A Dias, Pauline E Misson, Heiko Henze, Jürg Zumbrunn, Frank O Gombert, Daniel Obrecht, Peter Hunziker, Stefan Schauer, Urs Ziegler, Andres Käch, Leo Eberl, Kathrin Riedel, Steven J DeMarco, John A Robinson

Index: Science 327(5968) , 1010-1013, (2010)

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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 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.