Gramicidin A Mutants with Antibiotic Activity against Both Gram‐Positive and Gram‐Negative Bacteria

Abstract

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.

Cholesterol-induced deformation of the gramicidin-A channel inhibiting potassium ion binding and transport

“…[1,2] In biomedicine, gA not only serves as antibiotics against gram-positive bacteria but also functions as therapeutic agents for cancer. [3][4][5][6][7][8][9][10][11] Composed of 15 alternating L-and D-amino acids, gA can form either a single-stranded helical dimer in a head-to-head manner or a double-stranded intertwined helix in model membrane, [2,12] depending on the property of the solvent in which gA is dissolved before incorporated into the lipid bilayer. [13,14] The single-stranded gA dimer with a larger radius can transport monovalent cations such as potassium ions (K + ) and sodium ions (Na + ) whereas the double-stranded one is considered a non-channel conformation.…”

Effects of Calcium Ions on the Antimicrobial Activity of Gramicidin A

“…Gramicidin A has antibiotic and antimalarial activities [ 15 , 16 ]. Two mechanisms have been associated with antimicrobial activity [ 17 , 18 ].…”

Discovery of gramicidin A analogues with altered activities by multidimensional screening of a one-bead-one-compound library

“…1a ), discovered in 1939 from the soil bacterium Bacillus brevis 11 , 12 , was the first antibiotic to be manufactured commercially 13 , 14 . This peptidic natural product displays potent broad-spectrum antibiotic activity against Gram-positive strains, even multidrug-resistant strains 15 . Despite being an efficient antibiotic, 1 has the disadvantage of high hemolytic activity 16 .…”

“…Many effort has been made by chemists to investigate or control the ion channel function of 1 27 – 30 , collectively leading to the generation of approximately 350 artificial analogues (counted by SciFinder, 27 March 2020). Although these studies provided valuable information on the structure and channel function of 1 , only a few analogues have been identified to display different bioactivities from those of 1 15 , 31 – 34 . Because available SAR data are limited, it remains unclear how the ion channel function of 1 relates to its antibacterial and cytotoxic activities.…”