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TitleAn Antifungal with a Novel Mechanism of Action Discovered via Resistance Gene-Guided Genome Mining.
Journal, issue, pagesACS Cent Sci, Vol. 12, Issue 2, Page 197-207, Year 2026
Publish dateFeb 25, 2026
AuthorsBruno Perlatti / Sandeep Vellanki / Yalong Zhang / Yi-Ming Chiang / Yingxia Hu / Mengdi Yuan / Kyle Dunbar / Abigail Fine / Michelle F Grau / Sheena Li / Timothy O'Donnell / Rajani Shenoy / Hongtao Li / Hui Shi / Xia Xu / Zeyu Chen / Tara Arvedson / Yi Tang / Robert A Cramer / Victor Cee / Colin J B Harvey /
PubMed AbstractInvasive fungal infections claim over two million lives annually, a problem exacerbated by rising resistance to current antifungal treatments and an increasing population of immunocompromised ...Invasive fungal infections claim over two million lives annually, a problem exacerbated by rising resistance to current antifungal treatments and an increasing population of immunocompromised individuals. Despite this, antifungal drug development has stagnated, with few novel agents and fewer novel targets explored in recent decades. Here, we validate acetolactate synthase (ALS), an enzyme critical for branched-chain amino acid biosynthesis and absent in humans, as a promising target for new therapeutics. Using resistance gene-guided genome mining, we discovered a biosynthetic gene cluster in encoding HB-35018 (1), a novel spiro-cis-decalin tetramic acid that potently inhibits ALS. Biochemical and antifungal assays demonstrate that surpasses existing ALS inhibitors in efficacy against and other pathogenic fungi. Structural studies via cryo-electron microscopy reveal a unique covalent binding interaction between compound and ALS, distinct from known inhibitors, and finally, we demonstrate that ALS is essential for virulence in a mouse model of invasive aspergillosis. These findings position ALS as a promising target for antifungal development and demonstrate the potential of resistance gene-guided genome mining for antifungal discovery.
External linksACS Cent Sci / PubMed:41768770 / PubMed Central
MethodsEM (single particle)
Resolution2.36 - 2.76 Å
Structure data

73040

9yjz

EMDB-73040: cryoEM map of Apo Aspergillus fumigatus acetolactate synthase (ALS)
PDB-9yjz: cryoEM structure of Apo Aspergillus fumigatus acetolactate synthase (ALS)
Method: EM (single particle) / Resolution: 2.76 Å

73041

9yk0

EMDB-73041, PDB-9yk0:
cryoEM structure of Aspergillus fumigatus acetolactate synthase (ALS) in complex with a novel inhibitor
Method: EM (single particle) / Resolution: 2.36 Å

Chemicals

ChemComp-MG:
Unknown entry

ChemComp-TPP:
THIAMINE DIPHOSPHATE

ChemComp-FAD:
FLAVIN-ADENINE DINUCLEOTIDE / FAD*YM

PDB-1cxh:
COMPLEX OF CGTASE WITH MALTOTETRAOSE AT ROOM TEMPERATURE AND PH 9.6 BASED ON DIFFRACTION DATA OF A CRYSTAL SOAKED WITH MALTOHEPTAOSE

Source
  • aspergillus fumigatus (mold)
KeywordsPLANT PROTEIN / Branched-Chain Amino Acid Synthesis / antifungal target / herbicide target / anti fugal infection / natural product

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