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Related Experiment Video

Updated: Feb 7, 2026

Testing the Role of Multicopy Plasmids in the Evolution of Antibiotic Resistance
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Testing the Role of Multicopy Plasmids in the Evolution of Antibiotic Resistance

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An activity-resistance tradeoff constrains enzyme evolution.

Alexander W Sarkis, Jens Laurids Sørensen, Teis Esben Sondergaard

    Biorxiv : the Preprint Server for Biology
    |February 6, 2026
    PubMed
    Summary
    This summary is machine-generated.

    Antibiotic-producing fungi evolved self-resistance to mycophenolic acid (MPA) through a trade-off with enzyme efficiency. Pre-existing resistance to ribavirin-5'-monophosphate (RVP) may have paved the way for MPA resistance.

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    Area of Science:

    • Biochemistry
    • Evolutionary Biology
    • Genetics

    Background:

    • Antibiotic producers must possess self-resistance mechanisms to survive their own toxins.
    • The evolutionary origin of antibiotic self-resistance, particularly before antibiotic production, remains poorly understood.
    • Mycophenolic acid (MPA) is an antibiotic produced by fungi that inhibits inosine monophosphate dehydrogenase (IMPDH).

    Purpose of the Study:

    • To investigate the evolutionary origins of self-resistance to MPA in antibiotic-producing organisms.
    • To understand the relationship between MPA resistance and the catalytic efficiency of IMPDH.
    • To explore the role of other IMPDH inhibitors in the evolution of MPA resistance.

    Main Methods:

    • Phylogenetic analysis of IMPDH-B genes and fungal species.
    • Characterization of extant and resurrected ancestral IMPDH enzymes.
    • Enzyme activity assays to assess MPA and ribavirin-5 extquotesingle-monophosphate (RVP) resistance and catalytic efficiency.

    Main Results:

    • MPA resistance in IMPDH-B evolved between ancestral enzymes Anc2 and Anc3, coinciding with a significant loss of catalytic efficiency.
    • A persistent trade-off between MPA resistance and enzyme activity was observed across all tested enzymes.
    • Both extant and ancestral IMPDH-Bs exhibited resistance to RVP, with RVP resistance potentially preceding MPA resistance.

    Conclusions:

    • The evolution of MPA resistance in fungi is constrained by a trade-off with IMPDH catalytic efficiency.
    • Pre-existing resistance to RVP may have created a permissive evolutionary background for the subsequent development of MPA resistance.
    • Horizontal gene transfer events likely played a significant role in the distribution of IMPDH-B genes across fungal lineages.