Abstract
Nisin inhibits bacterial growth by generating pores in cell membrane and interrupting cell-wall biosynthesis through specific lipid II interaction. However, the role of the hinge region and C-terminus residues of the peptide in antibacterial action of nisin is largely unknown. Here, using molecular dynamics simulations and experimental approach, we report that at high concentration regimes of nisin, interaction with phospholipids may equally deform the bacterial cell membranes even under significantly varying amounts of lipid-II. Membrane thinning, destabilization and decrease in lipid density depend on the degree of oligomerization of nisin. Growth kinetics of Bacillus subtilis and Escherichia coli interestingly show recovery by extended lag phase under low concentrations of nisin treatment while high concentrations of nisin caused decrease in cell viability as recorded by striking reduction in membrane potential and surface area. The significant changes in the dipole potential and fluorescence anisotropy were observed in negatively charged membranes in the absence of lipid-II with increasing concentration of nisin. The identical correlation of cell viability, membrane potential dissipation and morphology with the concentration regime of nisin, in both Bacillus subtilis (lipid II rich) and Escherichia coli (lipid II impoverished), hints at a non-specific physical mechanism where degree of membrane deformation depends on degree of crowding and oligomerization of nisin.
Highlights
Nisin, a 34 amino acid residue long cationic peptide, belongs to class I pore-forming bacteriocins and displays a unique pore-forming activity against bacteria which is known to be enhanced in the presence of lipid II8,9
We investigate the direct role of nisin-phoshpholipid interaction in driving lipid II-independent contribution to the membrane deformation apart from established lipid II-dependent mechanism
Using Molecular Dynamics (MD) simulations and experimental approaches we show that nisin can deform the membrane through non-specific interaction with phospholipids upon crowding on the membrane surface of both gram-positive and gram-negative bacteria
Summary
A 34 amino acid residue long cationic peptide, belongs to class I pore-forming bacteriocins and displays a unique pore-forming activity against bacteria which is known to be enhanced in the presence of lipid II8,9. Dipole potential and anisotropy measurements in reconstituted membranes strongly suggest nisin interaction with negatively charged membrane even in the absence of lipid II. These findings demonstrate that nisin exposure in a collective population of bacteria is heterogeneous; the time-scale of death of the bacteria depends on the surface bound density of nisin. We propose a non-specific physico-chemical model of nisin action (that may be lipid II mediated) that drives membrane deformation dependent on its membrane surface bound density by showing the correlation between nisin concentration, membrane destabilization (surface/dipole potential, fluorescence anisotropy and intensity) and cell viability. This study will provide a complementary perspective to the existing molecular understanding of nisin mediated antibacterial activity
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