Frank Otto Gombert - Peptidomimetic Antibiotics Target Outer-Membrane Biogenesis in Pseudomonas aeruginosa

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      Publication Details (including relevant citation   information):

      Srinivas,   N.; Jetter, P.; Ueberbacher, B. J.; Werneburg, M.; Zerbe, K.;   Steinmann, J.; Van der Meijden, B.; Bernardini, F.; Lederer, A.;   Dias, R. L. A.; Misson, P. E.; Henze, H.; Zumbrunn, J.; Gombert,   F. O.; Obrecht, D.; Hunziker, P.; Schauer, S.; Ziegler, U.; Kach,   A.; Eberl, L.; Riedel, K.; DeMarco, S. J.; Robinson, J. A.   Peptidomimetic Antibiotics Target Outer-Membrane Biogenesis in   Pseudomonas aeruginosa. Science 2010,  327, 1010-1013.


      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.

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