title: 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.
authors.affiliation: Department of Chemistry, Merkert Chemisty Center, Boston College, 2609 Beacon St., Chestnut Hill, MA, 02461, USA.
authors.forename: Breanna L
authors.initials: BL
authors.lastname: Zerfas
authors.affiliation: Department of Chemistry, Merkert Chemisty Center, Boston College, 2609 Beacon St., Chestnut Hill, MA, 02461, USA.
authors.forename: Yechaan
authors.initials: Y
authors.lastname: Joo
authors.affiliation: Department of Chemistry, Merkert Chemisty Center, Boston College, 2609 Beacon St., Chestnut Hill, MA, 02461, USA. jianmin.gao@bc.edu.
authors.forename: Jianmin
authors.identifier: http://orcid.org/0000-0001-9341-1287
authors.initials: J
authors.lastname: Gao
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D002463:Cell Membrane Permeability / Q000187:drug effects; D006090:Gram-Negative Bacteria / Q000187:drug effects*; D006094:Gram-Positive Bacteria / Q000187:drug effects*; D006096:Gramicidin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D006461:Hemolysis; D008239:Lysine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D006096:Gramicidin; D008239:Lysine
keywords: Gram-negative bacteria; antimicrobial peptides; gramicidin A; membrane permeability; methicillin-resistant Staphylococcus aureus (MRSA)