Unanticipated global emergence and evolution of Pneumocystis jirovecii mutations and resistance driven by a human-targeted drug

Nearly all known cases of antimicrobial resistance have been linked to agents that directly target microbes. This paradigm overlooks other drivers of microbial evolution and resistance. Here, we report compelling evidence of resistance-associated mutations in Pneumocystis jirovecii , a high-priority fungal pathogen designated by WHO as having unknown resistance. These mutations emerged under selective pressure from mycophenolic acid (MPA), a widely used immunosuppressant not used for Pneumocystis pneumonia (PCP) treatment. A potent inhibitor of inosine monophosphate dehydrogenase (IMPDH), MPA has been linked to altered P. jirovecii susceptibility in solid organ transplant (SOT) recipients. Genetic analysis of 163 P. jirovecii samples from PCP outbreaks in SOT recipients and nontransplant controls across six countries identified six impdh mutations, four of which were previously unreported. These mutations showed strong associations with prior MPA exposure, geographic segregation, and temporal shifts. They arose independently in 11 distinct strains worldwide between 2005 and 2019, with evidence of switching within and between strains, suggesting ongoing adaptive evolution. Structural modeling predicted that these mutations reduced IMPDH stability and MPA binding; accordingly, all mutations conferred MPA resistance in enzyme inhibition assays. Our findings uncover the unanticipated global emergence of multiple resistance-associated mutations in P. jirovecii driven by a human-targeted immunosuppressant, likely conferring a survival advantage in SOT recipients and facilitating transmission and outbreaks. These results challenge the current status quo on P. jirovecii ’s unknown resistance, calling for reevaluating immunosuppressive strategies and infection control measures and highlighting the broader potential for other pathogens to evolve under selective pressures imposed by human-targeted therapies.

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Journal
Science Translational Medicine
Published
2026-09-16
DOI
https://doi.org/10.1126/scitranslmed.adz4471
Primary Topic
Pneumocystis jirovecii pneumonia detection and treatment
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article
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article

Unanticipated global emergence and evolution of Pneumocystis jirovecii mutations and resistance driven by a human-targeted drug

Jannik Helweg‐Larsen, Grace Handley, Nicolas J. Mueller, Joseph A. Kovacs et al.
Science Translational Medicine
Pneumocystis jirovecii pneumonia detection and treatment
article

Unanticipated global emergence and evolution of Pneumocystis jirovecii mutations and resistance driven by a human-targeted drug

Jannik Helweg‐Larsen, Grace Handley, Nicolas J. Mueller, Joseph A. Kovacs, Cédric Hirzel, Weizhong Chang, Alexia Cusini, Norihiko Goto, Benjamin Spielman, Liang Ma, Thomas Fehr, Xilong Deng, Shinichi Oka, Sara Gianella, Andreas Arendtsen Rostved, Laurence Huang, Hirohisa Yazaki, Andreas Sing, Lizbeth Hedstrom, Lingai Pan, Monica Sassi, Tomozumi Imamichi, Steven M. Ewell, Peng Li, Yubao Wang, Regina Konrad, Ming Hao, Akanchhya Khanal, Laura F. Walsh, Marwan M. Azar, Junfeng Sun
article en

Abstract

Nearly all known cases of antimicrobial resistance have been linked to agents that directly target microbes. This paradigm overlooks other drivers of microbial evolution and resistance. Here, we report compelling evidence of resistance-associated mutations in Pneumocystis jirovecii , a high-priority fungal pathogen designated by WHO as having unknown resistance. These mutations emerged under selective pressure from mycophenolic acid (MPA), a widely used immunosuppressant not used for Pneumocystis pneumonia (PCP) treatment. A potent inhibitor of inosine monophosphate dehydrogenase (IMPDH), MPA has been linked to altered P. jirovecii susceptibility in solid organ transplant (SOT) recipients. Genetic analysis of 163 P. jirovecii samples from PCP outbreaks in SOT recipients and nontransplant controls across six countries identified six impdh mutations, four of which were previously unreported. These mutations showed strong associations with prior MPA exposure, geographic segregation, and temporal shifts. They arose independently in 11 distinct strains worldwide between 2005 and 2019, with evidence of switching within and between strains, suggesting ongoing adaptive evolution. Structural modeling predicted that these mutations reduced IMPDH stability and MPA binding; accordingly, all mutations conferred MPA resistance in enzyme inhibition assays. Our findings uncover the unanticipated global emergence of multiple resistance-associated mutations in P. jirovecii driven by a human-targeted immunosuppressant, likely conferring a survival advantage in SOT recipients and facilitating transmission and outbreaks. These results challenge the current status quo on P. jirovecii ’s unknown resistance, calling for reevaluating immunosuppressive strategies and infection control measures and highlighting the broader potential for other pathogens to evolve under selective pressures imposed by human-targeted therapies.

Science Translational MedicineVol. 18(867)
University of Bern (CH), University of Electronic Science and Technology of China (CN), University of California, San Francisco (US), GlaxoSmithKline (United Kingdom) (GB), University Hospital of Bern (CH), Tianjin Medical University General Hospital (CN), Copenhagen University Hospital (DK), University of California System (US), University of California San Diego (US), Fourth People's Hospital of Sichuan Province (CN), Health and Safety Authority (IE), University Hospital of Zurich (CH), Akebono Clinic (JP), The Affiliated Yongchuan Hospital of Chongqing Medical University (CN), Frederick National Laboratory for Cancer Research (US), Institute for Health Economics and Policy (JP), Nagoya Central Hospital (JP), Kantonsspital Graubünden (CH), National Institutes of Health Clinical Center (US), Guangzhou Eighth People's Hospital (CN), Brandeis University (US), Chongqing Medical University (CN), Guangzhou Medical University (CN)
Good health and well-being
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Pneumocystis jirovecii pneumonia detection and treatment
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