How Colistin Disrupts Gram-Negative Bacteria
Colistin, also known as polymyxin E, belongs to the polymyxin class of antibiotics and acts primarily on Gram-negative bacteria, such as Pseudomonas aeruginosa and Acinetobacter baumannii. Its core action is the catastrophic disruption of the bacterial cell membranes, making it a crucial tool against multidrug-resistant pathogens. The polycationic and amphipathic nature of colistin allows it to destabilize the negatively charged bacterial surface.
Initial Electrostatic Interaction and Membrane Disruption
The primary step involves colistin's electrostatic interaction with the lipopolysaccharide (LPS) in the outer membrane of Gram-negative bacteria. The LPS layer is stabilized by divalent cations. Colistin's positive charge binds to the negative phosphate groups of LPS's lipid A, displacing the stabilizing cations and weakening the outer membrane. This leads to "self-promoted uptake" of colistin, where its hydrophobic tail further disrupts the membrane.
Damage to the Cytoplasmic Membrane and Cell Lysis
After crossing the outer membrane, colistin attacks the cytoplasmic membrane. Its detergent-like action disrupts the phospholipid bilayer, causing leakage of cellular contents and ultimately leading to cell lysis and death. Research indicates colistin also targets LPS that accumulates in the cytoplasmic membrane, challenging older theories of non-specific detergent action.
Other Potential Mechanisms of Action
Beyond membrane disruption, colistin has other antibacterial effects. It has anti-endotoxin activity by binding to and neutralizing lipid A, which can trigger septic shock. Colistin can also induce oxidative stress by generating reactive oxygen species, causing damage to bacterial DNA, proteins, and lipids. Some studies suggest it can inhibit respiratory enzymes, disrupting energy production.
Comparative Mechanism of Colistin on Bacterial Membranes
| Feature | Outer Membrane (OM) Interaction | Cytoplasmic Membrane (CM) Interaction |
|---|---|---|
| Primary Target | Negatively charged LPS, specifically the lipid A component. | Phospholipid bilayer and accumulated LPS. |
| Initial Action | Electrostatic binding and competitive displacement of stabilizing divalent cations ($Ca^{2+}$, $Mg^{2+}$). | Detergent-like disruption and LPS targeting. |
| Mechanism | Destabilizes the LPS monolayer, increasing permeability. | Causes leakage of intracellular contents and cell lysis. |
| Contributing Factors | Hydrophobic acyl chain insertion. | Oxidative stress and enzyme inhibition may contribute. |
| Consequence | Allows for "self-promoted uptake". | Lethal damage, resulting in bacterial death. |
The Problem of Colistin Resistance
Colistin resistance is a growing concern, limiting its use. Resistance primarily involves modifications to the LPS structure.
- LPS Modification: Bacteria modify LPS to reduce its negative charge, decreasing colistin binding. This is often done by adding cationic groups like phosphoethanolamine (pEtN) and 4-amino-4-deoxy-L-arabinose (L-Ara4N) to lipid A.
- Chromosomal Mutations: Mutations in regulatory systems like PhoPQ and PmrAB can cause these LPS modifications.
- Plasmid-Mediated Resistance (mcr genes): Mobile mcr genes, such as mcr-1, encode enzymes that add pEtN to lipid A, conferring transferable resistance between species.
- Loss of LPS: Some bacteria lose their LPS layer, removing colistin's primary target.
Conclusion
Colistin's mechanism of action is a multi-step process targeting the cell membranes of Gram-negative bacteria. It starts with electrostatic interaction and disruption of the outer membrane's LPS, followed by destabilization of the cytoplasmic membrane, leading to cell lysis. Additional effects like anti-endotoxin activity and oxidative stress enhance its bactericidal power. However, the rise of multidrug-resistant bacteria and resistance mechanisms, particularly plasmid-mediated mcr genes, challenge colistin's efficacy. Continued research is vital for preserving colistin's role as a last-resort antibiotic. Further information on colistin's action and resistance can be found on PubMed Central.
