The scale of the analysis is itself remarkable. Drawing on publications indexed in PubMed, Embase, and Web of Science, and following the PRISMA reporting guidelines, the research team—which included investigators from Shahid Beheshti University of Medical Sciences, Tehran University of Medical Sciences, Alborz University of Medical Sciences, and collaborating institutions in Iran—extracted resistance data from clinical isolates worldwide. Of the 245 included studies, 106 focused on K. pneumoniae, 89 on P. aeruginosa, 42 on E. coli, and 8 on S. maltophilia. Pooled prevalence estimates with 95 percent confidence intervals were calculated using random-effects meta-analysis in Stata version 18, with subgroup analyses stratified by continent, publication year, and the laboratory method used to detect resistance. That methodological detail matters: colistin susceptibility testing is notoriously unreliable with automated systems, and the gold-standard broth microdilution method is not always used, a source of heterogeneity the authors explicitly accounted for.

The headline numbers tell a story of divergent fortunes across species. The pooled global prevalence of colistin resistance stood at 5.9 percent for P. aeruginosa and 4.0 percent for E. coli—troubling, but still comparatively contained. K. pneumoniae, however, showed a pooled resistance rate of 20.6 percent, meaning that in the hospital wards captured by these studies, roughly one in five clinical isolates of this notoriously drug-resistant pathogen no longer responded to the antibiotic of last resort. Most alarming of all was S. maltophilia, an opportunistic pathogen that disproportionately infects immunocompromised and critically ill patients, where pooled resistance reached 38.5 percent. Because colistin is among the few options available for some S. maltophilia infections, a resistance rate approaching four in ten isolates represents a genuinely precarious therapeutic situation.

Geography sharpened the picture considerably. At the country level, higher prevalence estimates for P. aeruginosa were observed in Canada, India, and Spain; for K. pneumoniae in Brazil and Greece; and for E. coli in China and Turkey. For S. maltophilia, elevated rates were reported in countries where data exist but remain sparse, including Colombia, Thailand, and Hungary. This patchiness is a finding in its own right. The authors highlight the scarcity of data from Oceania in particular, along with the limited number of studies from several countries, as critical gaps in global surveillance. Resistance does not respect borders, and the regions where no one is measuring may be precisely where the problem is spreading unobserved.

Beneath the prevalence statistics lies a second layer of the analysis: the molecular identity of the resistant strains. Using multilocus sequence typing and, in a subset of studies, whole-genome sequencing, the review identified dominant clonal lineages driving colistin resistance. In P. aeruginosa, sequence type ST235 dominated overwhelmingly, accounting for 58.0 percent of typed resistant isolates—a clone with an international reputation for virulence and multidrug resistance. In K. pneumoniae, ST101 was the most frequently identified lineage at 29.0 percent, a sequence type long associated with carbapenem-resistant hospital outbreaks. In E. coli, two lineages shared the spotlight, with ST131 and ST69 each representing 10.6 percent of typed isolates. ST131 in particular is among the most successful extraintestinal pathogenic E. coli clones ever documented, and its presence among colistin-resistant isolates underscores how resistance genes can piggyback on globally disseminated successful strains.

The genetics of resistance itself emerged as perhaps the most consequential finding. Colistin kills bacteria by binding to lipopolysaccharide, the negatively charged lipid anchor of the outer membrane of Gram-negative bacteria. Resistance typically arises when bacteria chemically modify that target—adding phosphoethanolamine or other moieties that reduce colistin binding. Since the discovery in 2015 that this modification can be encoded by plasmid-borne mcr genes, the specter of horizontally transferable colistin resistance has haunted antimicrobial resistance research: unlike chromosomal mutations, plasmid-mediated resistance can jump between species and strains with alarming efficiency. The meta-analysis found that the mcr-1 variant—the first and still most widespread plasmid-mediated colistin resistance gene—was overwhelmingly dominant. It accounted for 100 percent of resistant P. aeruginosa isolates in which mcr variants were reported, 97.8 percent of resistant E. coli isolates, and 57.4 percent of resistant K. pneumoniae isolates. Notably, no mcr variants were reported in S. maltophilia, whose resistance presumably rests on other mechanisms, including intrinsic and adaptive modifications of its lipopolysaccharide or related membrane structures.

The predominance of mcr-1 across three of the four species carries a double warning. First, it suggests that the plasmid-mediated resistance machinery that first emerged in livestock and food animals has fully entrenched itself in human clinical populations worldwide. Second, because mcr-1 typically co-occurs on plasmids carrying other resistance determinants—carbapenemases, extended-spectrum beta-lactamases—its continued dominance implies that colistin resistance is not traveling alone but as part of packages of pan-drug resistance. The scenario that infectious disease specialists have long feared, in which a plasmid carrying both a carbapenemase gene and an mcr gene arrives in a single successful K. pneumoniae clone, is not hypothetical; the high resistance rates in K. pneumoniae documented in this analysis suggest it is already unfolding in substantial pockets of the world.

The detection methods underlying these estimates also reveal a structural weakness in the field. Across the included studies, colistin susceptibility was assessed by broth microdilution—the reference method recommended by clinical standards bodies—by epsilometer gradient tests, and by a range of disk diffusion and automated systems, the latter of which are known to produce discordant results for polymyxins. The subgroup analyses by detection method, alongside stratification by continent and publication year, exposed meaningful heterogeneity in the pooled estimates, a reminder that part of the global variation in reported resistance reflects not just true biological differences but differences in how laboratories measure the phenomenon. Minimum inhibitory concentration testing, MALDI-TOF-based identification of isolates, pulsed-field gel electrophoresis, and whole-genome sequencing were variably deployed across the evidence base, with higher-resolution methods concentrated in wealthier countries—a further source of surveillance bias.

What emerges from the synthesis is a call to action that the authors frame in explicitly global terms. Colistin resistance, they conclude, remains a significant and expanding threat among major Gram-negative pathogens worldwide, with substantial geographical variation in resistance prevalence, sequence type distribution, and mcr gene profiles. The high resistance rates observed in certain regions, they argue, emphasize the urgent need for coordinated international surveillance, antimicrobial stewardship programs, and targeted infection control strategies to limit the dissemination of colistin-resistant strains. In practical terms, that means standardized polymyxin susceptibility testing in all clinical laboratories, aggressive screening and containment of high-risk clones such as ST235 P. aeruginosa and ST101 K. pneumoniae, and rational restriction of colistin use in both human medicine and agriculture, where the drug’s continued use in animal feed remains a plausible reservoir for mcr-1.

For clinicians, the message is sobering but not fatalistic. A global resistance rate of 4 to 6 percent in E. coli and P. aeruginosa still leaves colistin useful in most infections caused by those organisms, provided susceptibility is confirmed by reliable testing. But the 20.6 percent rate in K. pneumoniae and the 38.5 percent rate in S. maltophilia transform treatment decisions in settings where those pathogens dominate—intensive care units, neonatal units, and wards housing ventilator-associated pneumonia, contexts the review’s underlying studies frequently describe. Empirical use of colistin without susceptibility confirmation is increasingly a gamble in high-prevalence regions. And because the review’s evidence base draws on studies published through 2025, the picture it paints is a floor, not a ceiling; the trajectory of resistance documented in year-stratified analyses points upward for at least some organism-region combinations.

The study also carries a quieter methodological legacy. By systematically cataloguing sequence types and mcr variants across a quarter-century of literature and four bacterial species simultaneously, it provides a baseline against which future surveillance can be measured—a common reference frame for a problem that has too often been studied in fragments. As the authors and the broader antimicrobial resistance community emphasize, the antibiotics pipeline remains thin, and for some MDR Gram-negative infections there is nothing behind colistin at all. Protecting the last line of defense, this analysis makes clear, is no longer an abstract aspiration but an epidemiologically urgent, geographically mapped, and molecularly characterized imperative.

Antibiotic resistance represents one of the most formidable challenges confronting modern medicine, with certain pathogens developing insurmountable defenses against nearly all known antibiotics. Even more insidious is the phenomenon of cross-protection wherein resistant bacteria degrade antibiotics in their immediate environment, effectively creating a drug-free haven that shelters susceptible bacteria from eradication. This communal resistance complicates infection control and accelerates the persistence and evolution of multi-drug resistant strains within polymicrobial communities.

The research, spearheaded by Nikol Kadeřábková and Chris Furniss, pivots on targeting a crucial protein-folding system vital for the functionality of bacterial resistance enzymes, especially β-lactamases. These enzymes, produced by pathogens such as Stenotrophomonas maltophilia, dismantle β-lactam antibiotics—widely used drugs including penicillins and cephalosporins—thereby neutralizing their therapeutic impact. The premise builds on the concept that by obstructing this cellular machinery, resistance enzymes lose their functional integrity, rendering bacteria vulnerable once more to antibiotic assaults.

To simulate clinically relevant conditions, the researchers employed synthetic polymicrobial communities comprising Pseudomonas aeruginosa and Stenotrophomonas maltophilia, bacteria commonly co-isolated from cystic fibrosis lung infections. Pseudomonas aeruginosa, predominantly treated with β-lactams, frequently evolves resistance partially driven by cross-protection from S. maltophilia, a species notorious for its near pan-antibiotic resistance mediated by robust β-lactamase production. This dual-species model allowed for an intricate exploration of how disrupting protein-folding mechanisms could simultaneously sensitize both pathogens and extinguish the protective interactions between them.

Functional disruption of the protein-folding gene, achieved through precise genetic deletions, resulted in the inactivation of β-lactamases and a marked resensitization of both bacterial species to β-lactam antibiotics. These findings validate the centrality of protein folding in maintaining resistance capabilities and underscore the therapeutic potential of targeting this system. Crucially, this genetic approach also illuminated the role of cross-protection in fostering multi-species resistance, as interference with protein folding nullified the protective benefits S. maltophilia confers upon P. aeruginosa.

Beyond genetic perturbations, the study made a significant leap by demonstrating that chemical inhibitors targeting the same protein-folding system could recapitulate the effect of gene deletions. This chemical inhibition reinstated antibiotic susceptibility without the need for genetic modification, highlighting a tangible path toward drug development and clinical application. These inhibitors effectively dismantled resistance enzyme activity whilst simultaneously breaking down the defensive synergy bacteria exploit in polymicrobial infections.

To validate their approach in vivo, the researchers utilized an infected wax moth larvae model, an established proxy for bacterial pathogenesis. Treatment with the protein-folding inhibitor in combination with antibiotics conferred significantly improved outcomes by not only eradicating individual species but also impeding their cooperative resistance mechanisms. This experimental evidence strengthens the concept that interventions disrupting bacterial enzyme maturation can profoundly influence the dynamics of polymicrobial infections.

The implications of this work extend well beyond cystic fibrosis, given that protein-folding systems and β-lactamase-mediated resistance are ubiquitous across a broad spectrum of Gram-negative bacteria. By targeting a shared vulnerability, this strategy holds promise for restoring the potency of β-lactam antibiotics against a wide array of multidrug-resistant bacterial infections—offering hope amidst a global health crisis propelled by the dwindling arsenal of effective antimicrobials.

This pioneering research highlights a paradigm shift in antimicrobial strategy: instead of developing new antibiotics, it focuses on disarming bacterial resistance mechanisms to make existing drugs effective again. The precise targeting of the bacterial protein-folding apparatus that matures resistance-conferring enzymes paves the way for adjunct therapies that could be administered alongside conventional antibiotics. Such combination treatments may rejuvenate the efficacy of frontline drugs while circumventing the lengthy and costly pipeline of new antibiotic discovery.

The study also emphasizes the importance of modeling infections as complex, polymicrobial ecosystems rather than isolating single species. Real-world infections often involve intricate bacterial communities where interspecies interactions modulate drug resistance and pathogenicity. Addressing these interactions is essential for the development of therapies that can effectively disrupt cross-protection and curb the spread of resistance within microbial populations.

Looking forward, research efforts will likely focus on optimizing protein-folding inhibitors for human use, assessing potential toxicity profiles, and exploring their efficacy across diverse bacterial species and infection models. This holistic approach promises to contribute substantially to antimicrobial stewardship by revitalizing the therapeutic utility of β-lactams and potentially delaying the emergence of resistance.

“In targeting the protein-folding machinery essential for antibiotic resistance enzymes, we unlock a previously underappreciated vulnerability in multidrug-resistant pathogens,” says Despoina Mavridou, co-author and assistant professor at UT Austin. “Our findings open exciting possibilities for adjunct therapies that, when combined with standard antibiotics, could transform the treatment landscape for stubborn infections, including those complicating cystic fibrosis.”

As antibiotic-resistant infections continue to escalate globally, discoveries like this not only illuminate new scientific frontiers but also reinforce the critical need for integrated strategies tackling microbial resistance at multiple levels. By undermining both individual bacterium defenses and their collective cooperation, novel therapeutic paradigms emerge—offering a beacon of hope in the fight against one of medicine’s most urgent challenges.

Subject of Research: Cells

Article Title: Antibiotic potentiation and inhibition of cross-resistance in pathogens associated with cystic fibrosis

News Publication Date: 21-Apr-2026

Web References:
DOI 10.7554/eLife.91082.2.sa4

Image Credits: Nikol Kadeřábková

Keywords: Antibiotic resistance, Drug resistance, Cell biology, Molecular biology, Cystic fibrosis