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Title: The zeamine antibiotics affect the integrity of bacterial membranes
Authors: Masschelein, Joleen
Clauwers, Charlien
Stalmans, Karen
Nuyts, Koen
De Borggraeve, Wim
Briers, Yves
Aertsen, Abram
Michiels, Chris
Lavigne, Rob # ×
Issue Date: 2015
Publisher: American Society for Microbiology (ASM)
Series Title: Applied and Environmental Microbiology vol:81 issue:3 pages:1139-1146
Article number: AEM.03146-14
Abstract: The zeamines (zeamine, zeamine I and zeamine II) constitute an unusual class of cationic polyamine-polyketide-nonribosomal peptide antibiotics produced by Serratia plymuthica RVH1. They exhibit potent bactericidal activity, killing a broad range of Gram-negative and Gram-positive bacteria including multidrug-resistant pathogens. Examination of their specific mode of action and molecular target revealed that the zeamines affect the integrity of cell membranes. The zeamines provoke rapid release of carboxyfluorescein from unilamellar vesicles with different phospholipid compositions, demonstrating that they can interact directly with the lipid bilayer in the absence of a specific target. DNA, RNA, fatty acid and protein biosynthetic processes ceased simultaneously at sub-inhibitory levels of the antibiotics, presumably as a direct consequence of membrane disruption. The zeamine antibiotics also facilitated uptake of small molecules such as 1-N-phenylnaphtylamine, indicating their ability to permeabilize the Gram-negative outer membrane (OM). The valine-linked polyketide moiety present in zeamine and zeamine I was found to increase the efficiency of this process. In contrast, translocation of the large hydrophilic fluorescent peptidoglycan binding protein PBDKZ-GFP was not facilitated, suggesting that the zeamines cause subtle perturbation of the OM rather than drastic alterations or defined pore formation. At zeamine concentrations above those required for growth inhibition, membrane lysis occurred as indicated by time-lapse microscopy. Together, these findings show that the bactericidal activity of the zeamines derives from generalized membrane permeabilization, which is likely initiated by electrostatic interactions with negatively charged membrane components.
URI: 
ISSN: 0099-2240
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Molecular Design and Synthesis
Centre for Food and Microbial Technology
Laboratory of Experimental Radiotherapy
Division of Gene Technology (-)
× corresponding author
# (joint) last author

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