Colistin resistance in Pseudomonas aeruginosa driven by chromosomal mutations and rising mcr-1 genes, global review finds

Colistin, an antibiotic reserved for some of the hardest-to-treat bacterial infections, is losing ground against Pseudomonas aeruginosa, according to a systematic review and meta-analysis published in Discover Bacteria in January 2026. The study, led by Tsegahun Asfaw Abebe of the University of Ghana with colleagues including Andrew M. Edwards and Abiola Isawumi, screened 1318 records and analyzed 40 studies following PRISMA guidelines, with the literature search conducted between March 1 and April 30, 2025. The analysis shows that resistance to this last-resort drug is driven mainly by mutations in two chromosomal gene pairs, pmrAB and phoPQ, while plasmid-borne mcr genes, especially mcr-1, are appearing with increasing frequency across human, animal and environmental sources.

The stakes are high because P. aeruginosa is an opportunistic pathogen that causes serious infections in immunocompromised patients. The review notes that P. aeruginosa infections are estimated to be associated with over 300,000 annual deaths and that the bacterium sits at the top of the WHO priority list of pathogens requiring urgent research and clinical interventions. Colistin, or polymyxin E, kills bacteria by targeting both the outer and inner cytoplasmic membrane, disrupting cell envelope integrity and ultimately causing bacterial lysis. It was rarely used in human medicine for decades because of toxicity, but the limited pipeline of new antibiotics active against multidrug-resistant Gram-negative bacteria has pushed clinicians back to it, and the World Health Organization has classified colistin as a critically important antibiotic for human medicine while the World Organization for Animal Health has flagged its critical relevance for veterinary medicine.

Mechanistically, the review describes a layered defense system. The leading mechanism of P. aeruginosa colistin resistance is chromosomal mutation, most commonly in the pmrAB and phoPQ operons, which encode two-component systems. These mutations activate the arnBCADTEF and pmrCAB operons, leading to modification of lipopolysaccharide by addition of a 4-amino-4-deoxy-L-arabinose moiety or cationic phosphoethanolamine in the lipid A structure, changes that reduce the drug’s binding to the bacterial surface. More recent studies have also implicated mutations in parRS, colRS and cprRS. The parRS operon not only drives colistin resistance by activating arnBCADTEF but also promotes a multidrug-resistant phenotype through hyperproduction of the efflux pumps MexXY and MexEF-OprN and downregulation of the outer membrane porin OprD, enhancing resistance to aminoglycosides, fluoroquinolones, cefepime and carbapenems.

Across the 40 included studies, pmrA/B emerged as the most frequently reported mutated gene, detected in 17 studies, or 42.5 percent. Mutations in the pmrA/B system were found not only in colistin-resistant isolates but also in susceptible ones, a detail the authors highlight as complicating interpretation. The regulatory genes phoP/Q were reported as mutated in 12 studies, or 30 percent, the parR/S system in 9 studies, or 22.5 percent, with the specific H398R mutation in parS appearing in 5 studies, and the arn operon arnBCADTEF-ugd in 10 studies, or 25 percent. Among plasmid-mediated resistance genes, mcr-1 was reported in 15 studies, or 37.5 percent, while mcr-2, mcr-3, mcr-5 and mcr-7 were rarely reported.

The chronological analysis adds a worrying dimension: plasmid-mediated mcr genes emerged later in P. aeruginosa than in the Enterobacteriaceae family. Initially, colistin resistance in P. aeruginosa clinical isolates was primarily associated with chromosomal mutations in genes such as pmrAB and phoPQ. Over time, plasmid-mediated resistance has emerged with increasing detection of mcr-1, now reported in human, animal and environmental isolates. The authors frame this as adaptive evolution toward mobile resistance, with critical implications for global surveillance, since plasmid-borne genes can in principle move between bacterial species, although they note that mcr genes remain relatively uncommon in P. aeruginosa compared with Enterobacteriaceae.

Geographically, the picture is uneven. Colistin resistance driven by chromosomal mutations was predominantly reported in Europe. Norway recorded a 3 percent resistance rate from 67 clinical samples, Spain documented 2.7 percent from 150 clinical isolates, and the United Kingdom reported a higher prevalence of 34.4 percent from 61 veterinary-associated companion animal and human clinical samples. Outside Europe, the United States reported 16.7 percent from 227 bloodstream isolates, Haiti reported 8 percent from 50 clinical samples, and China showed 0.3 to 2.2 percent resistance from various clinical samples. In Egypt, prevalence ranged from 2.1 to 26.9 percent across studies of 48 and 26 samples respectively, with mcr genes reported from clinical samples, milk from mastitic cows and faecal samples from wild birds. In Pakistan, mcr genes were reported from clinical isolates and poultry secretions, with resistance prevalence ranging from 0.3 to 11.9 percent across studies of 1076 and 84 samples. Brazil showed 1 percent resistance from 99 clinical samples but 44 percent from 25 animal ear swabs from cases of otitis, while Saudi Arabia reported 9.5 percent from 74 clinical isolates and Iran reported 4 to 14.5 percent from 101 and 69 clinical samples respectively.

The meta-analysis also mapped high-risk clones, particularly ST235, ST111 and ST357. ST235 was the most frequently reported clone, detected in Norway, Spain, Turkey, Iran, India, Saudi Arabia, South Korea and the United States. ST111 was reported from Norway, the United States and Spain, while ST357 appeared in India, Saudi Arabia and Qatar. The authors report that high-risk clones showed cross-continental transmission across European, Latin American and Asian-pacific countries, and that resistance to colistin was reported for additional sequence types including ST233, ST244, ST308, ST175, ST277, ST654 and ST298. These clones are associated with multidrug-resistant and extensively drug-resistant phenotypes, and the review describes virulence factors such as ExoU, a potent phospholipase toxin linked to high cytotoxicity, and ExoS, a bifunctional enzyme that disrupts host cell signalling and immune responses, as further enhancing their pathogenic potential.

Co-resistance emerged as one of the most alarming findings. Most colistin-resistant P. aeruginosa isolates also carried genes for β-lactamases, carbapenemases, overexpressed efflux pumps, loss of the outer membrane porin OprD and aminoglycoside-modifying enzymes. Colistin resistance was co-reported with resistance to fluoroquinolones, chloramphenicol, sulphonamides, tetracyclines, fosfomycin and macrolides, producing multidrug-resistant and extensively drug-resistant phenotypes. The authors note that β-lactamase genes are frequently co-located with mcr-1 on transposons or integrons, enabling co-transfer, and that these co-resistant strains are associated with frequent diagnostic delays because conventional methods often fail to detect the full resistance profile. The concurrent resistance to carbapenems and colistin dramatically narrows therapeutic options, often forcing reliance on older, more toxic antibiotics, which can lead to delayed effective treatment, increased risk of therapeutic failure and elevated mortality.

Statistically, the review found that resistance rates varied significantly across regions, with the highest variability in Asia and Europe, and significant heterogeneity with I² above 80 percent and p below 0.001, though overall regional differences in the pooled resistance rate were negligible with p equal to 0.8257. Heterogeneity was also high by study design and sample size, with large cohorts showing I² of 95.5 percent, and evidence of publication bias was detected with p equal to 0.0001, with funnel plot asymmetry indicating possible underreporting of negative results or gaps in surveillance. The authors attribute the heterogeneity to divergent selection pressures, colistin usage policies, prescribing practices, uneven stewardship implementation, and the lack of standardization in susceptibility testing, since pooled data merge results from reference broth microdilution with less reliable alternatives such as gradient strips and commercial automated systems.

The review’s limitations are substantial and acknowledged by the authors. Heterogeneous testing methods, small sample sizes in some studies, incomplete data on mutation detail and clonal types, and the mixing of human, animal and environmental isolates with different selection pressures all constrain comparability. Because the included studies were not designed to assess colistin resistance within individual high-risk clones, the exact prevalence of resistance in each clone could not be determined. Most importantly, the significant under-representation of data from Africa, South America and Oceania means the global summary likely underestimates the true burden in those regions and limits generalizability. Among the 40 studies, 32 came from human sources, 5 from animals and 3 from the environment, and most studies used broth microdilution, with 27 of 40 studies, or 67.5 percent, employing that reference method. The authors call for regulated colistin use, enhanced genomic surveillance, regular antibiotic stewardship programs, rapid diagnostics and novel therapies, warning that without coordinated global action, common P. aeruginosa infections could become routinely fatal in a post-antibiotic era.

Subject of Research: Systematic review and meta-analysis of molecular mechanisms and genetic epidemiology of colistin resistance in Pseudomonas aeruginosa

Article Title: Molecular mechanisms and genetic epidemiology of colistin resistance in Pseudomonas aeruginosa: a systematic review and meta-analysis

Article References: Abebe, T. A., Awandare, G. A., Edwards, A. M., & Isawumi, A. (2026). Molecular mechanisms and genetic epidemiology of colistin resistance in Pseudomonas aeruginosa: a systematic review and meta-analysis. Discover Bacteria, 3(1), Article 5. https://doi.org/10.1007/s44351-026-00044-y

Image Credits: AI Generated

DOI: 10.1007/s44351-026-00044-y

Keywords: Pseudomonas aeruginosa, colistin resistance, pmrAB, phoPQ, mcr-1, high-risk clones, ST235, antimicrobial resistance, systematic review, meta-analysis, One Health, co-resistance