Lipid-II Independent Antimicrobial Mechanism of Nisin Depends On Its Crowding And Degree Of Oligomerization

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.

Postantibiotic and Sub-MIC Effects of Exebacase (Lysin CF-301) Enhance Antimicrobial Activity against Staphylococcus aureus

“…As with the membrane permeabilization study described above, the possibility that the assay buffer used here affected the CF-301 and/DAP cannot be discounted; however, the very rapid onset of depolarization is consistent with the timing of cell envelope destabilization observed by TEM in Fig. 2 The pore-forming toxin, nisin, was additionally used a positive control because of its ability to rapidly dissipate transmembrane electrostatic potential (31). In Fig.…”

“…Overall, our findings highlight the remarkable potential of this lysin (and possibly the lysin class) to serve as an adjunctive therapeutic strategy used in addition to conventional antibiotics to treat life-threatening bacterial infections, particularly those which result in substantial morbidity and mortality despite treatment with conventional antibiotics. Further studies to elucidate the mechanism(s) of postexposure and sub-MIC effects reported here, including the nature of cell envelope damage, the potential role for induction of the cell wall stress stimulon (31)(32)(33)(34), and the specific impact on cell wall anchored and secreted virulence factors, will be pursued.…”

Fabrication of biocompatible and efficient antimicrobial porous polymer surfaces by the Breath Figures approach

“…This result can be explained considering the mechanisms of action of Nisin. Nisin bactericidal activity is directly related to the oligomerization form of the Nisin for the stabilization of the permeabilizing pores [38]. Thus the amount of Nisin and surface coverage density will be critical to achieve efficient bactericidal activity.…”

Nisin penetratesStaphylococcus aureusbiofilms but shows differences in killing effects against sessile and planktonic cells

“…Moreover, although in rod-shaped bacteria new peptidoglycan precursors can be added either into their lateral wall or at their division septum, in S. aureus the cell wall biosynthesis occurs predominantly in the division septum, which is rich in lipid II (53, 54). Lipid II is the main target of nisin in bacterial cells that act as an anchor during the pore formation in the cytoplasmic membrane (34, 51, 55). This uneven distribution of lipid II during cell wall biosynthesis in S. aureus was also confirmed with telavancin, a semisynthetic derivative of vancomycin with high affinity to lipid II, which was shown to bind mostly to lipid II in the division septum of exponentially growing S. aureus cells causing membrane depolarization (54).…”