Statistical design, structural analysis, and in vitro susceptibility assay of antimicrobial peptoids to combat bacterial infections

Antimicrobial peptoids (ampetoids) have been established as a new and attractive class of antibiotic agent to combat bacterial infections with high bioavailability, strong metabolic stability, and low in vivo toxicity. Here, we reported successful design of short ampetoids by integrating chemometrics/cheminformatics techniques and in vitro susceptibility test. In the procedure, a novel panel of natural and N ‐substituted amino acid descriptors was derived by principal component analysis of hundreds of constitutional, topological, geometrical, and physicochemical properties, which was then used to characterize and model the statistical regression relationship between the structural feature and antibacterial activity of known antimicrobial peptides. The resulting best quantitative structure‐activity relationship predictor confirmed by Monte Carlo cross validation was employed to perform high‐throughput virtual screening against a combinatorial ampeptod library, from which five ampeptod candidates were identified and their antibacterial potencies against two clinical bacterial strains, that is, Staphylococcus aureus ATCC33591 and Pseudomonas aeruginosa ATCC27853, were measured using a standard microtiter broth dilution method. Consequently, three ampeptoids (IK‐ N ssb‐ N Lys‐VRK‐ N ssb‐NH 2 , KYW‐ N His‐N‐ N spe‐RLR‐NH 2 , and N Lys‐L‐ N Lys‐W‐ N smb‐IKRW‐NH 2 ) were found to have high antibacterial activity with minimum inhibitory concentration <30 µg/lm against the two strains. Molecular dynamics simulations revealed that two of the three potent ampeptoids can fold into a typical amphipathic helix that allows them to interact directly with and then destruct microbial membranes, while another is unstructured in water environment and possesses a hybrid sequence pattern mixing with hydrophobic and hydrophilic residues. Copyright © 2016 John Wiley & Sons, Ltd.