Abstract
Antimicrobial
drug resistance is a looming health crisis facing
us in the modern era, and new drugs are urgently needed to combat
this growing problem. Synthetic mimics of antimicrobial peptides have
recently emerged as a promising class of compounds for the treatment
of persistent microbial infections. In the current study, we investigate
five cyclic
N
-alkylated amphiphilic 2,5-diketopiperazines
against 15 different strains of bacteria and fungi, including drug-resistant
clinical isolates. Several of the 2,5-diketopiperazines displayed
activities similar or superior to antibiotics currently in clinical
use, with activities coupled to both the cationic and hydrophobic
substituents. All possible stereoisomers of the lead peptide were
prepared, and the effects of stereochemistry and amphiphilicity were
investigated via 1D and 2D NMR spectroscopy, solution dynamics, and
membrane interaction modeling. Clear differences in solution structures
and membrane interaction potentials explain the differences seen in
the bioactivity and physicochemical properties of each stereoisomer.