What is the mechanism of action of Polymyxin B?

Polymyxin B Mechanism of Action

Polymyxin B kills Gram-negative bacteria by binding to lipid A in lipopolysaccharide (LPS) and increasing bacterial cell membrane permeability, leading to cell death 1.

Primary Mechanism

Polymyxin B is a cationic polypeptide antibiotic that targets the outer membrane of Gram-negative bacteria through a specific molecular interaction:

• Targets lipid A: The drug binds to lipid A, which is the conserved membrane anchor of lipopolysaccharide in the bacterial outer membrane 2
• Increases membrane permeability: This binding disrupts the membrane structure, causing increased permeability that leads to bacterial cell death 1
• Displaces counterions: Polymyxin B displaces divalent cations (like Mg²⁺ and Ca²⁺) that normally stabilize LPS molecules 3

Detailed Molecular Actions

The mechanism involves a sophisticated three-state process:

1. Initial electrostatic binding: The positively charged polymyxin B electrostatically approaches the negatively charged LPS molecules 4
2. Membrane insertion: Following transient binding, the drug inserts into the membrane via its acyl chain 5
3. Super-stoichiometric accumulation: Polymyxin B forms long-lived clusters that accumulate in the membrane, creating a sustained bactericidal effect 2

Effects on Membrane Structure

Outer membrane disruption: Polymyxin B loosens the LPS bilayer by:

• Creating lipid packing defects 3
• Decreasing the orientation order of LPS tails 3
• Breaking the synchronous movement of LPS molecules, making them diffuse more randomly 5
• Inducing LPS aggregation in a concentration-dependent manner 4

Inner membrane effects: Paradoxically, polymyxin B stiffens the phospholipid inner membrane rather than disrupting it by:

• Filling lipid packing defects 3
• Increasing membrane bending rigidity 3
• Restricting lipid diffusion 3

Spectrum of Activity

• Active against: Almost all Gram-negative bacilli (except Proteus species) 1
• Resistant organisms: All Gram-positive bacteria, fungi, and Gram-negative cocci 1
• Bactericidal action: The combined effects on both outer and inner membranes deprive bacteria of biological activity, achieving sterilization rather than simple membrane rupture 3

Important Clinical Caveat

The drug loses 50% of its activity in the presence of serum, resulting in relatively low active blood levels despite administration 1. This pharmacokinetic limitation is why polymyxin B is often used in combination therapy for serious infections and why adjunctive inhaled administration may be beneficial for pneumonia 6.