Some of the most important drugs of the last hundred years came out of fungi. Penicillin, of course — but also cephalosporins, cyclosporine (which made organ transplantation practical), the statins, griseofulvin (the first oral antifungal), and much of modern chemotherapy scaffolding. Fungi are chemical factories, and they’ve been generous ones.
The uncomfortable fact underneath that history is that we’ve only ever been reading a small fraction of what fungi can produce. Genome sequencing has shown, over and over, that fungal genomes contain many more biosynthetic “gene clusters” than the compounds we’ve ever isolated from them. Most of that chemistry sits silent — the pathways exist, but nothing in the lab’s growth conditions wakes them up. A new paper in Nature Biotechnology from Xue “Sherry” Gao’s group at the University of Pennsylvania describes a tool that changes that.
What fPE7max does
The team, with postdoctoral researcher Chunxiao Sun as first author, built a fungal prime-editing system they call fPE7max. Prime editing (originally developed for mammalian cells by the Liu lab at the Broad Institute) is a next-generation of the CRISPR toolkit that can make specific base changes, small insertions, or small deletions without cutting both strands of DNA — much cleaner than earlier CRISPR-Cas9 approaches and, crucially, less prone to unwanted edits.
Adapting prime editing to filamentous fungi — the moulds and mushrooms most of the interesting drug chemistry comes from — has been technically hard. fPE7max is their answer: a version tuned to fungal biology that achieves roughly 90% editing efficiency, which is remarkable for this kind of tool in this kind of organism.
The demonstration is where the paper gets interesting. The team went after a single gene called laeA — a well-known master regulator that helps keep many secondary metabolism pathways switched off in fungi under normal conditions. Edit laeA, and the silent chemistry starts producing.
What they found
Across several fungal species, precision edits to laeA unlocked biosynthesis of 18 complex molecules. Of those:
- 8 were entirely new chemical structures — not previously described in the literature.
- 3 showed selective anti-cancer activity against human breast, hepatic, and leukaemia cell lines in laboratory assays.
That “selective” is important. It means the compounds killed cancer cells more efficiently than they killed normal cells — the therapeutic window drug developers spend most of their time chasing.
Why this is genuinely exciting
The world’s antibiotic and antifungal pipelines are thin. Fungal secondary metabolism has been staring at us for decades with the promise of “there’s more in there” — but we couldn’t switch it on efficiently or predictably. A high-efficiency prime editor for fungi flips that from a nice hypothesis into a systematic approach. Every unexplored fungal genome becomes a search space.
What this means for dermatology
Directly? Nothing in the next year. This is a research tool that produces early-stage drug candidates — the road from a novel molecule to a topical or systemic medicine takes a decade of medicinal chemistry, formulation, safety testing, and clinical trials, and most candidates fall out along the way.
Indirectly? A lot, potentially. Modern dermatology relies heavily on drugs that started as fungal or microbial products — antifungals themselves, of course, but also broader anti-inflammatory and immunomodulatory therapies. The pipeline that eventually gives us better antifungals, better acne antibiotics that don’t drive resistance, and better systemic therapies for immune-mediated skin conditions runs through discoveries like this. Every “new chemical structure” here is a small chance at something.
We’ll be watching what comes next.