How Does Colistin Work? Mechanism of Action, Per the Research

Colistin, also known as polymyxin E, is a prescription antibiotic of the polymyxin class. Product labelling describes the marketed form as colistimethate sodium, a sulfomethylated derivative of colistin, and states that it is indicated for the treatment of acute or chronic infections caused by sensitive strains of certain Gram-negative bacilli, particularly Pseudomonas aeruginosa. This page summarises what the published pharmacology literature reports about how the molecule acts on bacterial cells. It does not describe how any product is used. This page is for educational purposes only and is not medical advice; consult a licensed physician about any medicine, indication or treatment decision.

The molecule and its class

Reviews of polymyxin chemistry describe colistin as a cyclic lipopeptide carrying a fatty acyl tail and multiple positively charged diaminobutyric acid residues, a structure that researchers have linked directly to its activity against Gram-negative organisms (PMID 31364069). A 2020 extended review of the 2000–2019 literature characterised colistin as an older agent that returned to clinical attention because of multidrug-resistant Gram-negative infections, and summarised its chemistry, spectrum and pharmacology in that context (PMID 32284036). Clinical pharmacology reviews also distinguish colistin from polymyxin B, noting that the two differ in a single amino acid and, importantly, in the form in which each reaches the patient — colistimethate sodium being an inactive precursor that converts to colistin in the body, whereas polymyxin B is supplied in its active form (PMID 26488563).

The established mechanism: lipid A binding and outer-membrane disruption

The mechanism described most consistently across the polymyxin literature is a physicochemical attack on the Gram-negative outer membrane rather than inhibition of a classical enzyme or ribosomal target (PMID 31364069). It is usually presented as a sequence of steps.

Step 1 — electrostatic attraction to lipopolysaccharide

The outer leaflet of the Gram-negative outer membrane is dominated by lipopolysaccharide (LPS), whose lipid A anchor carries phosphate groups that give the surface a strong net negative charge. Reviews reported that the polycationic polymyxin molecule is drawn to these anionic phosphate groups on lipid A, an interaction treated in the literature as the initial and defining binding event (PMID 32284036). Because this target is a structural lipid rather than a protein receptor, the literature does not describe a conventional receptor–ligand signalling cascade in the bacterium (PMID 31364069).

Step 2 — displacement of divalent cations

Adjacent LPS molecules are normally cross-bridged by divalent calcium and magnesium ions. Mechanistic reviews described polymyxins as competitively displacing those stabilising cations, which loosens the tightly packed LPS lattice and destabilises the membrane (PMID 32284036). The evidence that this interaction is decisive comes largely from the resistance side of the literature: when bacteria reduce the negative charge of lipid A, binding falls and susceptibility is lost (PMID 31364071).

Step 3 — permeabilisation and self-promoted uptake

Once the lattice is disturbed, the hydrophobic acyl tail of the molecule inserts into the membrane, increasing permeability and allowing further molecules to cross — a process the literature terms self-promoted uptake. Reviews reported that this leads to leakage of cell contents and bacterial death, and that the resulting activity is bactericidal and concentration-dependent (PMID 31364069). Related work on octapeptins, a structurally similar lipopeptide family, described the same general mode of envelope-targeting action and used it to explain activity against strains that have modified their lipid A (PMID 29848132).

Proposed mechanisms that remain under investigation

Beyond membrane disruption, reviews have catalogued secondary mechanisms that are discussed as hypotheses rather than settled pharmacology. These include oxidative damage to bacterial macromolecules following envelope injury and the neutralisation of free lipopolysaccharide, sometimes described as an anti-endotoxin effect (PMID 32284036). Work on next-generation polymyxin analogues noted that medicinal chemistry efforts have tried to separate antibacterial potency from toxicity, which implies the mechanistic basis of each is not fully resolved (PMID 31364086). Readers evaluating mechanism claims should note the distinction: lipid A binding and outer-membrane permeabilisation are the established account, while downstream oxidative and immunomodulatory effects are proposed extensions of it.

Why the spectrum is limited to Gram-negative organisms

Because the mechanism depends on LPS, the activity described in the literature is confined to Gram-negative bacteria that possess an LPS-bearing outer membrane; Gram-positive organisms, which lack that structure, are outside the spectrum (PMID 31364069). The 2020 extended review described colistin's relevance to multidrug-resistant Gram-negative pathogens, including Pseudomonas aeruginosa, Acinetobacter baumannii and carbapenem-resistant Enterobacteriaceae (PMID 32284036). Some genera are intrinsically outside that spectrum: a 2021 analysis of Aeromonas species examined intrinsic colistin resistance in that genus and the genetic determinants behind it (PMID 34205867).

How bacteria defeat the mechanism

Resistance research is, in effect, the strongest confirmation of the proposed mechanism, because nearly every described escape route alters the lipid A target itself.

Chromosomal regulation of lipid A

A review of polymyxin resistance mechanisms reported that two-component regulatory systems, notably PmrAB and PhoPQ, drive addition of 4-amino-4-deoxy-L-arabinose and phosphoethanolamine to lipid A, reducing its negative charge and therefore polymyxin binding (PMID 31364071). In Klebsiella pneumoniae, researchers specifically described loss or inactivation of the regulator mgrB among the chromosomal routes to colistin resistance (PMID 24794735).

Plasmid-mediated resistance: mcr-1 and mcr-2

In 2016 a microbiological and molecular study from China reported the first plasmid-mediated colistin resistance mechanism, MCR-1, a phosphoethanolamine transferase identified in isolates from animals and human beings, and showed it was transferable between strains (PMID 26603172). The study reframed colistin resistance from a chromosomal, strain-limited problem into a mobile one. A subsequent investigation characterised MCR-2 and deciphered its contribution to colistin resistance (PMID 28487432).

Newer and unusual routes

A 2024 report described phage-mediated colistin resistance in Acinetobacter baumannii, adding bacteriophage involvement to the known resistance repertoire (PMID 38301486). A 2025 study reported a colistin-induced transition from a non-mucoid to a mucoid phenotype in a resistant Pseudomonas aeruginosa ST3351 lineage, an adaptive change with implications for virulence (PMID 41144657).

• Target modification: lipid A decorated with L-Ara4N or phosphoethanolamine (PMID 31364071)
• Regulator loss: mgrB inactivation in K. pneumoniae (PMID 24794735)
• Mobile genes: mcr-1 (PMID 26603172) and mcr-2 (PMID 28487432)
• Intrinsic resistance: described in Aeromonas spp. (PMID 34205867)

Colistin compared with polymyxin B

An update comparing the two polymyxins reported that, despite near-identical antibacterial mechanisms, they differ pharmacologically because colistin is given as an inactive precursor that must convert in the body while polymyxin B is already active, and the review discussed how this difference affects attainment of active drug concentrations (PMID 26488563). That same comparison is frequently cited when researchers discuss differences in toxicity profiles between the two agents (PMID 26488563).

Nephrotoxicity and Neurotoxicity: What Studies Report

The toxicity literature is a central part of colistin pharmacology. The 2020 extended review reported that nephrotoxicity and neurotoxicity are the principal adverse effects associated with colistin and that toxicity concerns were a major reason the agent fell out of favour before its reintroduction for multidrug-resistant infections (PMID 32284036). The polymyxin B versus colistin update examined comparative toxicity between the two agents alongside their pharmacokinetic differences (PMID 26488563). Efforts to design novel polymyxin-like antibiotics have been framed explicitly around reducing this toxicity burden while retaining Gram-negative activity (PMID 31364086). Only a prescribing clinician can assess what these risks mean for an individual patient; this page does not provide that assessment.

Where the mechanism research is heading

Two directions appear in the cited literature. The first is structural modification of the polymyxin scaffold: a review of novel polymyxin-like antibiotics described discovery programmes aimed at analogues with improved profiles (PMID 31364086). The second is the octapeptin family, where researchers asked whether these lipopeptides could act against extensively drug-resistant bacteria, including strains that have modified lipid A and become polymyxin-resistant (PMID 29848132). Both lines rest on the same mechanistic premise described above.

Regulatory and practical context

Colistimethate sodium is a prescription medicine, available only through a licensed prescriber, and its approved indications are those stated on the product label for infections due to sensitive strains of specified Gram-negative bacilli. Nothing on this page addresses whether colistin is appropriate for any person, condition or organism, and no dosing information is provided here. Susceptibility testing, indication selection and monitoring are clinical decisions. For a broader overview of the molecule, see the colistin learn page.

References

• Emergence of plasmid-mediated colistin resistance mechanism MCR-1 in animals and human beings in China: a microbiological and molecular biological study (The Lancet Infectious Diseases, 2016)
• Colistin and its role in the Era of antibiotic resistance: an extended review (2000-2019) (Emerging Microbes & Infections, 2020)
• History, Chemistry and Antibacterial Spectrum (Advances in Experimental Medicine and Biology, 2019)
• Mechanisms of Polymyxin Resistance (Advances in Experimental Medicine and Biology, 2019)
• Colistin resistance in Klebsiella pneumoniae (International Journal of Antimicrobial Agents, 2014)
• Deciphering MCR-2 Colistin Resistance (mBio, 2017)
• Colistin Resistance in Aeromonas spp (International Journal of Molecular Sciences, 2021)
• Phage-mediated colistin resistance in Acinetobacter baumannii (Drug Resistance Updates, 2024)
• Colistin-induced transition from non-mucoid to mucoid phenotype in resistant Pseudomonas aeruginosa ST3351 (Virulence, 2025)
• Polymyxin B versus colistin: an update (Expert Review of Anti-infective Therapy, 2015)
• Discovery of Novel Polymyxin-Like Antibiotics (Advances in Experimental Medicine and Biology, 2019)
• Can octapeptin antibiotics combat extensively drug-resistant (XDR) bacteria? (Expert Review of Anti-infective Therapy, 2018)