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Effect of Ester to Amide or N-methyl Amide 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 to natural products, these derivatives may offer better stability under physiologically relevant...

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Bibliographic Details
Published in:ChemMedChem 2013-06, Vol.8 (8), p.1394-1402
Main Authors: Bionda, Nina, Fleeman, Renee M., Shaw, Lindsey N., Cudic, Predrag
Format: Article
Language:English
Online Access:Get full text
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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 to 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 have assessed the ability of cyclic lipodepsipeptide 1 , and its amide 2 , N-methyl amide 3 and linear peptide 4 analogues to interact with the cytoplasmic membranes of selected Gram-positive bacteria, as well as their bacteriostatic/bactericidal modes of action and in vivo potency 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 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-methyl amide bond 3 , or its hydrolysis 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 with different efficiencies reflecting their in vitro activities. Gaining more insights 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.
ISSN:1860-7179
1860-7187
DOI:10.1002/cmdc.201300173