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Gramicidin A Mutants with Antibiotic Activity against Both Gram‐Positive and Gram‐Negative Bacteria
Author(s) -
Zerfas Breanna L.,
Joo Yechaan,
Gao Jianmin
Publication year - 2016
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201500602
Subject(s) - antimicrobial , antibiotics , bacteria , microbiology and biotechnology , escherichia coli , gram negative bacteria , staphylococcus aureus , klebsiella pneumoniae , antimicrobial peptides , mutant , gram positive bacteria , biology , chemistry , biochemistry , genetics , gene
Antimicrobial peptides (AMPs) have shown potential as alternatives to traditional antibiotics for fighting infections caused by antibiotic‐resistant bacteria. One promising example of this is gramicidin A (gA). In its wild‐type sequence, gA is active by permeating the plasma membrane of Gram‐positive bacteria. However, gA is toxic to human red blood cells at similar concentrations to those required for it to exert its antimicrobial effects. Installing cationic side chains into gA has been shown to lower its hemolytic activity while maintaining the antimicrobial potency. In this study, we present the synthesis and the antibiotic activity of a new series of gA mutants that display cationic side chains. Specifically, by synthesizing alkylated lysine derivatives through reductive amination, we were able to create a broad selection of structures with varied activities towards Staphylococcus aureus and methicillin‐resistant S. aureus (MRSA). Importantly, some of the new mutants were observed to have an unprecedented activity towards important Gram‐negative pathogens, including Escherichia coli , Klebsiella pneumoniae and Psuedomonas aeruginosa .