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