The antibacterial mechanism of Nisin interacts with the cell membrane

Nisin, a natural antimicrobial peptide produced by Streptococcus lactis, exerts its antibacterial activity primarily through specific interactions with the cell membranes of susceptible microorganisms (mainly Gram-positive bacteria such as staphylococci, streptococci, and some bacilli). The entire process can be divided into four key stages: "recognition and binding - membrane structure disruption - leakage of intracellular contents - bacterial death." The specific mechanism of action and details of interactions with cell membranes are as follows:

I. Core of the Antibacterial Mechanism: Membrane-Dependent Targeted Action

Nisin's antibacterial effect is strictly target-dependent. It cannot penetrate the outer membrane of Gram-negative bacteria (because lipopolysaccharides in the outer membrane block its access to the inner membrane), while its action on Gram-positive bacteria is entirely centered on the cell membrane and relies on a specific receptor on the bacterial cell membrane—Lipid II. Lipid II is a key precursor in bacterial cell wall synthesis, composed of uridine diphosphate-N-acetylmuramic acid (UDP-MurNAc), a pentapeptide chain, and geranylgeranyl pyrophosphate (C55-PP). It is widely present on the outer surface of Gram-positive bacterial cell membranes and serves as the "molecular anchor" for Nisin's targeted binding.

II. Specific Interaction Process with Cell Membranes

1. Step 1: Receptor Recognition and Specific Binding

The Nisin molecular structure contains multiple lanthionine residues linked by thioether bonds, forming unique "cyclic peptide structures" (e.g., rings A, B, C). The amino acid sequences in the B and C ring regions (such as lysine and threonine residues) can form specific hydrogen bonds and electrostatic interactions with the pyrophosphate group and pentapeptide chain fragments in Lipid II molecules. This binding has high affinity, rapidly anchoring Nisin to the bacterial cell membrane surface, preventing its clearance by bacterial resistance mechanisms such as efflux pumps, and laying the foundation for subsequent membrane structure disruption. Notably, the distribution density of Lipid II on the cell membrane directly affects Nisin's efficiency—bacteria in the logarithmic growth phase, with active cell wall synthesis and higher Lipid II content, are significantly more sensitive to Nisin than those in the stationary phase.

2. Step 2: Formation of Membrane Perforation Channels

After Nisin binds to Lipid II, the resulting "Nisin-Lipid II complex" embeds into the phospholipid bilayer of the cell membrane through intermolecular hydrophobic interactions. The N-terminal of the Nisin molecule (containing hydrophobic amino acid residues) inserts into the hydrophobic region of the phospholipid bilayer, while the C-terminal remains exposed on the outer side of the cell membrane. Simultaneously, multiple "Nisin-Lipid II complexes" aggregate through their cyclic peptide structures to form transmembrane "pore complexes." These pores have a diameter of approximately 1-2 nm, and their formation does not rely on energy consumption, but rather on altering the lipid arrangement of the cell membrane—disrupting the ordered structure of the phospholipid bilayer and creating "leaks" in the originally tight membrane structure, providing channels for the leakage of intracellular contents.

3. Step 3: Osmotic Imbalance and Content Leakage

Once transmembrane pores form, the selective permeability of the bacterial cell membrane is completely destroyed: on one hand, extracellular water, sodium ions, and other small molecules flood into the cell along the osmotic gradient; on the other hand, key substances maintaining cellular life activities (such as potassium ions, amino acids, nucleotides, and ATP) continuously leak out of the cell through the pores. This osmotic imbalance causes bacterial cells to swell and the cell membrane to further rupture, while the loss of key substances directly inhibits bacterial energy metabolism (e.g., complete depletion of ATP), protein synthesis (insufficient amino acids), and nucleic acid replication (lack of nucleotides), ultimately depriving bacteria of normal physiological functions.

4. Step 4: Indirect Inhibition of Cell Wall Synthesis (Synergistic Antibacterial Effect)

In addition to directly damaging the cell membrane, nisin's binding to Lipid II indirectly interferes with bacterial cell wall synthesis. As a "transport carrier" for cell wall peptidoglycan synthesis, Lipid II must transport intracellularly synthesized peptidoglycan precursors to the outer surface of the cell membrane to participate in peptidoglycan chain cross-linking reactions. When Nisin binds to Lipid II, Lipid II's normal transport function is blocked, preventing peptidoglycan precursors from reaching the outside of the cell membrane and hindering cell wall synthesis. At this point, bacteria, with their cell membranes already damaged and unable to maintain cellular morphology and structural stability through the cell wall, undergo accelerated lysis and death, forming a synergistic antibacterial effect of "membrane disruption + cell wall synthesis inhibition."

III. Key Factors Affecting Interaction Efficiency

The efficiency of Nisin's interaction with cell membranes is not fixed and is regulated by multiple factors:

Lipid composition of the cell membrane: Bacterial cell membranes with higher unsaturated fatty acid content have more fluid phospholipid bilayers, making it easier for Nisin to embed and form pores; conversely, high saturated fatty acid content reduces membrane fluidity and weakens Nisin's effect.

pH and ionic strength: In acidic environments, nisin molecules carry a positive charge, enhancing electrostatic interactions with negatively charged cell membranes (phospholipid heads contain phosphate groups); high concentrations of divalent cations such as calcium and magnesium ions compete with nisin for binding to the cell membrane, reducing its binding efficiency.

Bacterial resistance mutations: Some resistant strains reduce Lipid II expression on the cell membrane or synthesize enzymes that degrade Nisin (e.g., Nisinase), weakening its interaction with the cell membrane and thus developing resistance.

The antibacterial mechanism of Nisin essentially involves specific binding to Lipid II on bacterial cell membranes, gradually disrupting membrane structure, causing osmotic imbalance, and synergistically inhibiting cell wall synthesis, ultimately leading to bacterial death. In this process, the interaction between Nisin and the cell membrane is the core link, whose efficiency directly determines the strength of antibacterial activity and provides a molecular-level theoretical basis for optimizing its applications (e.g., compounding with other antibacterial agents to enhance efficacy).