Journal
INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS
Volume 37, Issue 3, Pages 256-260Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ijantimicag.2010.11.024
Keywords
Antibiotic cyclic lipopeptides; Atomic force microscopy; Biosensor; C(55)-P; Friulimicin
Funding
- German Research Foundation [FOR 854, Be 2242/3-1]
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Friulimicin is a cyclic lipopeptide antibiotic, currently in clinical development, that possesses excellent activity against Gram-positive bacteria, including multiresistant strains. A recent study on the mode of action of friulimicin reported on the interference with bacterial cell wall biosynthesis via a calcium-dependent complexing of the bactoprenol phosphate carrier C(55)-P. The calcium dependency of this non-common targeted activity remains to be elucidated. In the present model membrane approach, the role of calcium for friulimicin targeting to C(55)-P was investigated by biosensor-based detection of binding affinities. The findings were supplemented by atomic force microscopy (AFM) and circular dichroism (CD) spectroscopy. Comparing the calcium salt of friulimicin with the calcium-free peptide, calcium appeared to be essential for friulimicin interaction with DOPC model membranes. The binding affinity was even higher in the presence of 0.1 mol% C(55)-P (0.21 mu M vs. 1.22 mu M), confirming the targeted mode of action. Binding experiments with supplemented calcium salts suggest (i) the phosphate group as the essential moiety of C(55)-P, referring to a bridging function of calcium between the negatively charged friulimicin and C(55)-P, and (ii) a structural effect of calcium shifting the peptide into a suitable binding conformation (CD spectra). AFM images confirmed that calcium has no, or only a minor, effect on the aggregate formation of friulimicin. These data shed new light on the mechanisms of antibacterial activity of friulimicin. (C) 2010 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.
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