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.

Against this backdrop, innovative strategies that can potentiate the antibacterial action of PMB while mitigating its risks are highly sought after. In a breakthrough study set to redefine the landscape of MDR bacterial treatment, researchers have unveiled an encouraging drug combination approach, linking PMB with tuspetinib (TUS) — a molecule hitherto renowned for its role in oncology. TUS, a selective FMS-like tyrosine kinase 3 (FLT3) inhibitor, is primarily deployed in combating acute myeloid leukemia (AML), celebrated for its targeted action and favorable safety spectrum. Yet, this novel investigation uncovers its surprising potential to bolster PMB’s efficacy against problematic bacterial strains, specifically Klebsiella pneumoniae, a notorious pathogen implicated in severe hospital-acquired infections.

Delving into the molecular interplay between bacterial resistance and drug action, the study elucidates the pivotal role of an enzyme called GlcNAc6P deacetylase (NagA) in PMB resistance. NagA, an essential enzyme in bacterial cell wall biosynthesis, emerges as a key facilitator of resistance mechanisms, allowing bacteria to withstand PMB’s otherwise lethal assault. Intriguingly, TUS appears to inhibit NagA’s enzymatic activity, thereby dismantling a crucial bacterial defense line. This mechanistic insight is a landmark discovery that expands our understanding of how chemical inhibition within bacterial metabolic pathways can be therapeutically exploited to circumvent resistance.

Klebsiella pneumoniae, especially clinical isolates resistant to polymyxin B, poses a profoundly difficult therapeutic challenge due to its ability to modify its outer membrane and avert antimicrobial penetration. The newly discovered synergy between TUS and PMB offers hope as it enhances bacterial susceptibility to PMB significantly, even in strains classified as resistant. This transformative finding not only rescues PMB’s efficacy but also suggests extending its clinical applications amidst an era shadowed by the looming threat of antibiotic failure.

To validate these compelling in vitro findings, researchers employed a mouse model of pulmonary infection, using a clinical PMB-resistant Klebsiella pneumoniae strain. The results were striking: combination therapy with TUS and PMB markedly improved infection clearance and survival rates compared to monotherapy with PMB alone. These experimental outcomes reinforce the therapeutic promise of this combination, potentially heralding a new standard in treating MDR bacterial lung infections, which remain daunting for critically ill patients.

Moreover, the study’s revelations resonate beyond the immediate application to Klebsiella pneumoniae. By targeting NagA, TUS might pave the way for repurposing kinase inhibitors and other small molecules to combat bacterial pathogens. This innovative paradigm represents a convergence of oncology and infectious disease pharmacology, proposing a fertile avenue for future drug discovery and repositioning initiatives.

Importantly, the safety profile of TUS as established in oncology settings lends substantial credence to its prospective deployment alongside PMB. Since PMB-associated nephrotoxicity often limits therapeutic strategies, the addition of TUS might allow for reduced PMB dosages without sacrificing antibacterial potency, thereby enhancing patient outcomes and minimizing adverse effects. This balance between efficacy and safety is critical in managing severe infections where treatment options are narrowly defined.

On a molecular scale, the inhibition of NagA by TUS underscores the intricate interplay between bacterial metabolism and antibiotic susceptibility. GlcNAc6P deacetylase catalyzes a key step in the peptidoglycan recycling pathway, impacting cell wall integrity and the bacterial response to external stressors, including antibiotics. Interrupting this pathway not only sensitizes bacteria to polymyxin B but could also disrupt broader bacterial survival strategies, setting a precedent for targeted metabolic intervention in antimicrobial therapy.

Given the growing prevalence of PMB resistance reported globally, this newly elucidated drug interaction heralds a timely advancement. It brings a new dimension to existing therapeutic regimens by leveraging a known kinase inhibitor’s unanticipated antimicrobial adjunct capabilities. The extension of TUS’s application into the antimicrobial sphere could inspire similar research into other kinase inhibitors, thereby widening the pharmacologic armamentarium against MDR infections.

In clinical contexts, the translation of these findings could revolutionize treatment protocols for infections caused by Gram-negative bacteria, notorious for their recalcitrance and adaptive commentary. The insights afforded by this research emphasize the importance of precision medicine approaches in infectious disease, integrating molecular targeting with traditional antimicrobial therapies to overcome resistance hurdles.

Furthermore, the prospect of combining drugs like TUS and PMB to exert a synergistic antibacterial effect is especially compelling in settings where therapeutic options are rapidly narrowing. Hospital environments battling outbreaks of resistant Klebsiella pneumoniae may benefit tremendously from such combination therapies by reducing mortality and curtailing infection spread.

Scaling the application of this research will require meticulous clinical trials to determine optimal dosing, safety parameters, and efficacy across diverse patient populations. However, the foundational work accomplished thus far lays a firm groundwork, exemplifying how strategic pharmacologic combinations can tackle the pressing threat posed by MDR pathogens, an area historically plagued by slow drug development.

This research also sheds light on the untapped potential residing in immune-modulating or oncological agents. Repurposing such drugs in infectious disease challenges traditional drug development paradigms and encourages cross-disciplinary innovation, essential for staying ahead in the race against antibiotic resistance.

In summary, the discovery that tuspetinib enhances the activity of polymyxin B by inhibiting the GlcNAc6P deacetylase NagA represents a pioneering stride forward in antibiotic potentiation strategies. It marries mechanistic insight with translational relevance, heralding a new frontier where targeted small molecules can rejuvenate the effectiveness of last-resort antibiotics against recalcitrant bacterial pathogens. As antibiotic resistance continues to threaten global health, such innovative approaches may prove invaluable in preserving and extending our antimicrobial arsenal.

Subject of Research: The study investigates the enhancement of polymyxin B’s antibacterial activity against multidrug-resistant Klebsiella pneumoniae through the inhibition of the GlcNAc6P deacetylase NagA by tuspetinib.

Article Title: Tuspetinib enhances the activity of polymyxin B by inhibiting the GlcNAc6P deacetylase.

Article References:
Ouyang, Y., Zhang, J., Cui, R. et al. Tuspetinib enhances the activity of polymyxin B by inhibiting the GlcNAc6P deacetylase. J Antibiot (2026). https://doi.org/10.1038/s41429-026-00920-4

Image Credits: AI Generated

DOI: 10 April 2026