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When Resistance and Virulence go hand in hand

The innovative TraDIS method provides new insights into the bacterium Klebsiella pneumoniae, which can cause severe infections

Antimicrobial resistance is one of the greatest challenges to global health. Researchers from the Department of “Epidemiology and Ecology of Antimicrobial Resistance” at the Helmholtz Institute for One Health (HIOH), led by Prof. Dr. Katharina Schaufler, PhD, have now uncovered a previously hidden link between antibiotic resistance and virulence in Klebsiella pneumoniae using the functional genomics method TraDIS (Transposon-directed insertion-site sequencing). Virulence describes the extent to which a pathogen can cause disease. The findings were published in the international journal Clinical Microbiology and Infection.

AMR: a global health challenge

Klebsiella pneumoniae is one of the most important causes of severe infections worldwide, particularly in healthcare settings (so-called nosocomial infections). From a One Health perspective, the bacterium is of particular relevance, as it occurs in the environment and can cause infections in humans and animals alike. Especially problematic are strains that are resistant to multiple antibiotics. In such cases, only very limited treatment options remain.

The reserve antibiotic cefiderocol is considered a promising treatment option against these resistant bacteria. It acts like a “Trojan horse”: it disguises itself as iron, which is essential for bacterial survival, is actively transported into the cell, and then kills the bacteria. However, in recent years, increasing reports have shown that resistance is now emerging even against cefiderocol.

Dot-like colonies of the bacterium Klebsiella pneumoniae on a CHROMagar™ plate. The blue coloration is characteristic of this pathogen. ©HIOH/Madeleine Paditz

TraDIS opens new insights

To understand the genetic basis that enables Klebsiella pneumoniae to become resistant to cefiderocol, the team used the method TraDIS (Transposon-directed insertion-site sequencing). This high-throughput technique allows researchers to systematically investigate genes across the entire bacterial genome. This way, the researchers were able to identify which genes are particularly important for the survival of Klebsiella pneumoniae under specific conditions—in this case, under antibiotic pressure.

Resistance and virulence are closely linked

The analysis revealed that a total of 299 genes in Klebsiella pneumoniae influence resistance to cefiderocol. In addition to known mechanisms—such as altered transport systems (e.g., for iron uptake) that reduce the entry of the antibiotic—the team also identified genes that control the bacterial capsule. This gel-like outer layer helps the bacteria protect themselves against external attacks. Further experiments showed that switching off the capsule-related genes leads to an increased production of the capsule. This makes Klebsiella pneumoniae not only more resistant to cefiderocol, but also more virulent—that is, more capable of causing severe infections. Experiments using an infection model with wax moth larvae (Galleria mellonella) confirmed that cefiderocol-resistant mutants cause significantly more severe infections.

DNA isolation in the laboratory to identify genes that influence antibiotic resistance and virulence in Klebsiella pneumoniae. ©HIOH/Madeleine Paditz

What these findings mean

For the first time, the study shows that resistance to cefiderocol may be directly linked to increased disease potential (pathogenicity). The enhanced protective layer of the bacteria—the capsule—not only limits the penetration of the antibiotic but also shields the pathogen from the host immune system. These findings highlight that antibiotic resistance should not be viewed in isolation but rather as closely linked to bacterial fitness and pathogenicity.

“Antimicrobial resistance can only be controlled through a holistic perspective,” emphasizes Prof. Schaufler. “Our study shows how closely resistance, virulence, and ecological fitness are intertwined—and why new therapeutic strategies must take these relationships into account.” 

The study represents an important outcome of functional omics research at HIOH, which investigates gene functions and how they influence bacterial traits, such as resistance and pathogenicity. The methodological foundation for this work was established during an eight-week research stay at the University of Copenhagen. In their Danish partner group “One Health Antimicrobial Resistance”, led by Prof. Luca Guardabassi, HIOH researchers learned the TraDIS method, further developed it, and adapted it specifically to their research questions.

A research stay at the University of Copenhagen, Denmark, during which the HIOH team learned the TraDIS method, laid the foundation for the present study. ©HIOH/GEAR

Study Information

The study was conducted in collaboration with an international research team from the following institutions:

Prof. Luca Guardabassi: One Health Antimicrobial Resistance Group, Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA

Institute of Medical Microbiology, University of Lübeck and University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany

Original publication

Müller JU, Eger E, Jana B, Schwabe M, Nurjadi D, Ma Y, Pirolo M, Guardabassi L, Schaufler K. The hidden link between cefiderocol resistance and increased virulence in Klebsiella pneumoniae: Insights from a TraDIS-based investigation. Clinical Microbiology and Infection (2026). DOI: 10.1016/j.cmi.2025.12.010

Further information

WHO bacterial priority pathogens list, 2024: Bacterial pathogens of public health importance to guide research, development and strategies to prevent and control antimicrobial resistance (ISBN: 978-92-4-009346-1) – Research article on the significance of various bacterial pathogens

Convergent Klebsiella pneumoniae strains belonging to a sequence type 307 outbreak clone combine cefiderocol and carbapenem resistance with hypervirulence – Research article on the interlinkage between antibiotic resistance and virulence 

Carbapenem- and cefiderocol-resistant Enterobacterales in surface water in Kumasi, Ashanti Region, Ghana – Research article on multidrug-resistant gut bacteria

Stephanie Markert

Press contact

Dr Stephanie Markert