Discovery of highly reactive self-splicing group II introns within the mitochondrial genomes of human pathogenic fungi

Nucleic Acids Res. 2021 Dec 2;49(21):12422-12432. doi: 10.1093/nar/gkab1077.


Fungal pathogens represent an expanding global health threat for which treatment options are limited. Self-splicing group II introns have emerged as promising drug targets, but their development has been limited by a lack of information on their distribution and architecture in pathogenic fungi. To meet this challenge, we developed a bioinformatic workflow for scanning sequence data to identify unique RNA structural signatures within group II introns. Using this approach, we discovered a set of ubiquitous introns within thermally dimorphic fungi (genera of Blastomyces, Coccidioides and Histoplasma). These introns are the most biochemically reactive group II introns ever reported, and they self-splice rapidly under near-physiological conditions without protein cofactors. Moreover, we demonstrated the small molecule targetability of these introns by showing that they can be inhibited by the FDA-approved drug mitoxantrone in vitro. Taken together, our results highlight the utility of structure-based informatic searches for identifying riboregulatory elements in pathogens, revealing a striking diversity of reactive self-splicing introns with great promise as antifungal drug targets.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Base Sequence
  • Blastomyces / genetics
  • Blastomyces / physiology
  • Coccidioides / genetics
  • Coccidioides / physiology
  • Computational Biology / methods
  • DNA, Mitochondrial / chemistry
  • DNA, Mitochondrial / genetics*
  • Genome, Mitochondrial / genetics*
  • Histoplasma / genetics
  • Histoplasma / physiology
  • Humans
  • Introns / genetics*
  • Mitosporic Fungi / classification
  • Mitosporic Fungi / genetics*
  • Mitosporic Fungi / pathogenicity
  • Mitoxantrone / pharmacology
  • Mycoses / microbiology
  • Nucleic Acid Conformation
  • RNA Splicing / drug effects
  • RNA Splicing / genetics*
  • Virulence / genetics


  • DNA, Mitochondrial
  • Mitoxantrone