Emerging antimicrobial resistant fungal pathogens are
a growing
threat, and fungicides with novel modes of action are urgently needed
to prevent critical failures in global food security. Fenpicoxamid,
the prodrug of UK-2A, is a member of a new class of antifungal agents
that displays no cross-resistance to other fungicides. Rational engineering
of its structure using a biosynthetic approach is a promising avenue
for developing more potent fungicides. Herein, through in
vitro enzymatic reconstitution, we elucidate the biosynthetic
pathway of UK-2A. Its biosynthesis involves a flexible AMP-binding
protein and dilactone formation
assembly enzymes that are able to select and incorporate highly diverse
substituted salicylic acids into the dilactone scaffold. By introducing
diverse salicylic acids into the in vitro biosynthetic
pathway, we successfully generate 14 novel deacyl UK-2A analogues.
This study reveals the flexibility of the biosynthetic pathway of
UK-2A and provides an effective solution to rationally engineer its
crucial C3 moiety.
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