1区 · 综合性期刊
Article
作者: Zerbe, Katja ; DeMarco, Steven J. ; Ziegler, Urs ; Van der Meijden, Benjamin ; Gombert, Frank O. ; Robinson, John A. ; Zumbrunn, Jürg ; Srinivas, Nityakalyani ; Werneburg, Martina ; Jetter, Peter ; Riedel, Kathrin ; Käch, Andres ; Hunziker, Peter ; Bernardini, Francesca ; Misson, Pauline E. ; Lederer, Alexander ; Dias, Ricardo L. A. ; Eberl, Leo ; Obrecht, Daniel ; Steinmann, Jessica ; Ueberbacher, Bernhard J. ; Henze, Heiko ; Schauer, Stefan
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.