Optimizing Antimicrobial Peptide Dendrimers in Chemical Space

We used nearest‐neighbor searches in chemical space to improve the activity of the antimicrobial peptide dendrimer (AMPD) G3KL and identified dendrimer T7, which has an expanded activity range against Gram‐negative pathogenic bacteria including Klebsiellae pneumoniae, increased serum stability, and...

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Bibliographic Details
Published inAngewandte Chemie Vol. 130; no. 28; pp. 8619 - 8623
Main Authors Siriwardena, Thissa N., Capecchi, Alice, Gan, Bee‐Ha, Jin, Xian, He, Runze, Wei, Dengwen, Ma, Lan, Köhler, Thilo, van Delden, Christian, Javor, Sacha, Reymond, Jean‐Louis
Format Journal Article
LanguageEnglish
Published Weinheim Wiley Subscription Services, Inc 09.07.2018
Subjects
Antiinfectives and antibacterials
Antimikrobielle Wirkstoffe
Chemischer Raum
Chemistry
Computer simulation
Dendrimere
Dendrimers
Dynamic structural analysis
Molecular chains
Molecular dynamics
Organic chemistry
Peptide
Virtuelles Screening
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Summary:We used nearest‐neighbor searches in chemical space to improve the activity of the antimicrobial peptide dendrimer (AMPD) G3KL and identified dendrimer T7, which has an expanded activity range against Gram‐negative pathogenic bacteria including Klebsiellae pneumoniae, increased serum stability, and promising activity in an in vivo infection model against a multidrug‐resistant strain of Acinetobacter baumannii. Imaging, spectroscopic studies, and a structural model from molecular dynamics simulations suggest that T7 acts through membrane disruption. These experiments provide the first example of using virtual screening in the field of dendrimers and show that dendrimer size does not limit the activity of AMPDs. Nächster‐Nachbar‐Suchverfahren im chemischen Raum wurden genutzt, um die Aktivität eines antimikrobiellen Peptid‐Dendrimers (AMPD) zu verbessern. Das identifizierte Analogon T7 hatte eine vergrößerte Aktivitätsspanne und war in vivo aktiv. In diesen Experimenten wurde erstmals ein virtuelles Screening von Dendrimeren genutzt. Dabei zeigte sich, dass die Größe des Dendrimers die Aktivität von AMPDs nicht begrenzt.
ISSN:0044-8249
1521-3757
DOI:10.1002/ange.201802837