Creating Novel Antimicrobial Peptides: From Gramicidin A toScreening a Cyclic Peptide Library
2017
As the threat of microbial resistance to antibiotics
grows, we must turn in new directions to find new drugs effective
against resistant infections. Antimicrobial peptides (AMPs) and
host-defense peptides (HDPs) are a class of natural products that
have been well-studied towards this goal, though very few have
found success clinically. However, as there is much known about the
behavior of these peptides, work has been done to manipulate their
sequences and structures in the search for more drug-like
properties. Additionally, novel sequences and structures mimicking
those seen in nature have been discovered and characterized.
Herein, we demonstrate our ability to finely tune the antimicrobial
activity of various peptides, such that they can be provided with
more clinically desirable characteristics. Our results show that
gramicidin A (gA) can be made to be less toxic via incorporation of
unnatural cationic amino acids. This is achieved by synthesizing
lysine analogues with diverse hydrophobic groups alkylated to the
side-chain amine. Through exploring different groups, we achieved
peptide structures with improved selectivity for bacterial over
mammalian membranes. Additionally, we were able to achieve novel
broad-spectrum gram-negative activity for gA peptides. In efforts
to combat bacterial resistance to cationic antimicrobial peptides
(CAMPs), we have directed our reported amine-targeting
iminoboronate chemistry towards neutralizing Lys-PG in bacterial
membranes. Originally incorporating 2-APBA into gA, we found this
to hinder the peptide’s activity. However, we were successful in
increasing the potency of gA3R, a cationic mutant of gA, towards S.
aureus by using a co-treatment of this peptide with a Lys-PG
binding structure. Currently, we are exploring this strategy
further. Finally, we describe our work towards establishing a novel
cyclic peptide library incorporating a 2-APBA warhead for
iminoboronate formation with a given target. In this, we have
achieved intermolecular reduction of iminoboronates, strengthening
the stringency of library screening. Although we were unsuccessful
in finding a potent hit for binding of the lipid II stem peptide,
screening against human transferrin yielded selective hits.
Currently we are investigating these hits to understand their
activity and therapeutic potential.
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