Peptidomimetic Antibiotics Target Outer-Membrane Biogenesis in Pseudomonas aeruginosa
2010
Srinivas, Nityakalyani | Jetter, Peter | Ueberbacher, Bernhard J. | Werneburg, Martina | Zerbe, Katja | Steinmann, Jessica | Van der Meijden, Benjamin | Bernardini, Francesca | Lederer, Alexander | Dias, Ricardo L.A. | Misson, Pauline E. | Henze, Heiko | Zumbrunn, Jürg | Gombert, Frank O. | Obrecht, Daniel | Hunziker, Peter | Schauer, Stefan | Ziegler, Urs | Käch, Andres | Eberl, Leo | Riedel, Kathrin | DeMarco, Steven J. | Robinson, John A.
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 β-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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