Effect of Ester to Amide or N-Methylamide Substitution on Bacterial Membrane Depolarization and Antibacterial Activity of Novel Cyclic Lipopeptides

Cyclic lipopeptides derived from the fusaricidin/LI‐F family of naturally occurring antibiotics represent particularly attractive candidates for the development of new antibacterial agents. In comparison with natural products, these derivatives may offer better stability under physiologically releva...

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Bibliographic Details
Published in:ChemMedChem 2013-08, Vol.8 (8), p.1394-1402
Main Authors: Bionda, Nina, Fleeman, Renee M., Shaw, Lindsey N., Cudic, Predrag
Format: Article
Language:eng ; ger
Subjects:
Amides - chemistry
Animals
Anti-Bacterial Agents - chemical synthesis
Anti-Bacterial Agents - chemistry
Anti-Bacterial Agents - pharmacology
Antibacterial activity
Antibiotics
Bacteria
biological activity
Cell Wall - drug effects
Circular Dichroism
depsipeptides
Esters
Gram-positive bacteria
Gram-Positive Bacteria - drug effects
Gram-Positive Bacteria - metabolism
isosteric analogues
Larva - microbiology
Lepidoptera - growth & development
Lipopeptides - chemical synthesis
Lipopeptides - chemistry
Lipopeptides - pharmacology
membranes
Methicillin-Resistant Staphylococcus aureus - drug effects
Methicillin-Resistant Staphylococcus aureus - isolation & purification
Microbiology
Models, Animal
Peptides
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Summary:Cyclic lipopeptides derived from the fusaricidin/LI‐F family of naturally occurring antibiotics represent particularly attractive candidates for the development of new antibacterial agents. In comparison with natural products, these derivatives may offer better stability under physiologically relevant conditions and lower nonspecific toxicity, while preserving their antibacterial activity. In this study we assessed the ability of cyclic lipodepsipeptide 1 and its analogues—amide 2, N‐methylamide 3, and linear peptide 4—to interact with the cytoplasmic membranes of selected Gram‐positive bacteria. We also investigated their bacteriostatic/bactericidal modes of action and in vivo potency by using a Galleria mellonella model of MRSA infection. Cyclic lipopeptides 1 and 2 depolarize the cytoplasmic membranes of Gram‐positive bacteria in a concentration‐dependent manner. The degree of membrane depolarization was influenced by the structural and physical properties of 1 and 2, with the more flexible and hydrophobic peptide 1 being most efficient. However, membrane depolarization does not correlate with bacterial cell lethality, suggesting that membrane‐targeting activity is not the main mode of action for this class of antibacterial peptides. Conversely, substitution of the depsipeptide bond in 1 with an N‐methylamide bond in 3, or its hydrolysis to peptide 4, lead to a complete loss of antibacterial activity and indicate that the conformation of cyclic lipopeptides plays a role in their antibacterial activities. Cyclic lipopeptides 1 and 2 are also capable of improving the survival of G. mellonella larvae infected with MRSA at varying efficiencies, reflecting their in vitro activities. Gaining more insight into the structure–activity relationship and mode of action of these cyclic lipopeptides may enable the development of new antibiotics of this class with improved antibacterial activity. To be or not to be active: A cyclic lipodepsipeptide and its amide analogue can depolarize the cytoplasmic membranes of Gram‐positive bacteria, whereas the N‐methylamide analogue is inactive. Membrane depolarization does not correlate with bacterial cell lethality, suggesting that membrane‐targeting activity is not the main mode of action for this class of antibacterial peptides.
ISSN:1860-7179
1860-7187
DOI:10.1002/cmdc.201300173