Peptidomimetic Antibiotics Target Outer-Membrane Biogenesis in Pseudomonas aeruginosa

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.

Peptidomimetic Antibiotics Target Outer-Membrane Biogenesis in Pseudomonas aeruginosa

2010

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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