Optimizing Antimicrobial Peptide Dendrimers in Chemical Space

Abstract

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.

Antimicrobial Peptide Dendrimer Chimera

“…Cyclic peptide 2 2 > 2000 bH1 [25] (L) 8 (BL) 4 (BF) 2 BK 22 (7) 2401.1/2400.0 16 n.d. [g] > 300 G3KL [34] (KL) 8 [34] (OF) 4 (KBL) 2 KKLK(C 10 ) 121 (42) 2395.61/2395.61 2 8 500 T7 [37] (KL) 8 Dendrimer chimera:…”

“…These results were in line with vesicle leakage data for the parent AMPDs G3KL, TNS18, and T7. [34,37] Note that activity of AMPs and AMPDs on neutral EYPC vesicles as well as their hemolysis activity generally increases with the fraction of hydrophobic residues.…”

“…To test whether the conformations observed by CD might indeed be present in dendrimer DC5, we performed molecular dynamics (MD) simulations using GROMACS [41] over 500 ns in pure water or with 20 % v/ v TFE starting from a conformer with (φ,ψ)-dihedral angles of all residues set in an α-helical conformation, as previously reported with other dendrimers. [34,37,42] Dendrimer DC5 rapidly unfolded in water to a hydrophobically collapsed conformation containing a mix of random coil and β-sheet structures, as indicated by the distribution of the Ramachandran angles, with leucines clustered towards the dendrimer center and Lys side chains pointing outwards, with a relatively compact conformation at an average radius of gyration of 1.2 nm (Figure 4a, 4b, 4d, and 4e).…”

“…[35,36] This approach led to the discovery of AMPD T7, a close analog of G3KL in which the two G1 dipeptides have been extended to lysine-leucine-leucine (KLL) tripeptides and the G0 core to a lysinelysine-leucine (KKL) tripeptide. [37] These seemingly minor modifications conferred additional activity to T7 against Klebsiella pneumoniae strains for which neither G3KL nor TNS18 showed any activity. However, T7 was inactive against S. aureus strains.…”

PubChem and ChEMBL beyond Lipinski

“…Analogs identified by MXFP similarity often comprise molecules with an overall molecular shape comparable to the query molecules, but with different structural composition. A good example is provided by searching NLP and NLC for analogs of T7 , an antimicrobial peptide dendrimer with an unusual multi‐branched peptide architecture which is active against multidrug resistant Gram‐negative bacteria . While the PubChem and ChEMBL webpages do not find any meaningful analogs for this query, returning smaller and linear peptides, our MXFP similarity search points to related polycationic dendritic molecules of very different detailed structure.…”