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
, 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
pneumonia (PCP) treatment. A potent inhibitor of inosine monophosphate dehydrogenase (IMPDH), MPA has been linked to altered
susceptibility in solid organ transplant (SOT) recipients. Genetic analysis of 163
samples from PCP outbreaks in SOT recipients and nontransplant controls across six countries identified six
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
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
'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.