Design of Trp-Rich Dodecapeptides with Broad-Spectrum Antimicrobial Potency and Membrane-Disruptive Mechanism

There
has recently been great concern regarding antibiotics due
to potential drug resistance and the impact of antibiotics on the
environment. Antimicrobial peptides are believed to have potential
as novel antimicrobial agents to address the problems of antibiotics.
Herein, we report a set of Trp-rich dodecapeptides derived from PMAP-36
that are based on the peptide folding principle and the amino acid
characteristics. An effective peptide design template, (WXYX)3, where X represents Arg or Lys and Y represents hydrophobic
or neutral amino acid, was summarized with the distribution of Trp
at H-bond formation sites along the α-helical structure. The
template peptide 6 (3W-2), with low amphipathicity, displayed
strong antimicrobial activity against laboratory strains and clinical
isolates while showing no cytotoxicity. Furthermore, 6 was able to suppress the emergence of antimicrobial resistance.
Membrane permeabilization assays and microscope observations revealed
the potent membrane-disruptive mechanism of 6. Overall,
this study diminishes the randomness in peptide design and provides
a strategy for generating effective antibiotic alternatives to overcome
antibiotic resistance.