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 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. Love thy neighbor: Nearest‐neighbor searches in chemical space were used to improve the activity of an antimicrobial peptide dendrimer (AMPD). This led to the identification of analogue T7, which shows an expanded activity range and promising in vivo activity. 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.