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Micafungin exposure drives multidrug resistance in Clavispora lusitaniae

Elizabeth Wash1,2, Nancy E Scott1,3, Katura Metzner1

  • 1University of Minnesota, Department of Microbiology and Immunology, Minneapolis, Minnesota, USA.

Biorxiv : the Preprint Server for Biology
|July 10, 2026
PubMed

Insights

Exposure to micafungin (MCF) alone can drive multidrug resistance in rare Candida species. A single mutation in ERG3 causes pan-antifungal resistance by altering cell membranes and walls, highlighting surveillance needs.

Area of Science:

  • Mycology
  • Molecular Biology
  • Antimicrobial Resistance

Background:

  • Fungal infections caused by rare Candida species are a growing global health concern.
  • Emerging multidrug resistance in these pathogens complicates treatment and increases mortality, especially in immunocompromised individuals.
  • The evolutionary pathways driving multidrug resistance in Candida species remain incompletely understood.

Purpose of the Study:

  • To investigate the selective forces driving multidrug resistance in *Clavispora (Candida) lusitaniae*.
  • To identify specific genetic mutations and physiological changes associated with antifungal resistance.
  • To understand the mechanisms by which *C. lusitaniae* develops resistance to multiple antifungal drug classes.

Main Methods:

  • Controlled evolution experiments involving exposure to micafungin (MCF).
  • Identification of point mutations in genes related to ergosterol biosynthesis (*ERG* genes), sterol trafficking (*OSH2*), and echinocandin drug target (*FKS1*).
  • Analysis of sterol content, cell wall composition (chitin), and antifungal susceptibility in evolved mutants.

Main Results:

  • Exposure to MCF monotherapy alone selected for multidrug resistance in *C. lusitaniae*.
  • Loss-of-function mutations in *ERG3* were identified as a primary, independent driver of pan-antifungal resistance to echinocandins, azoles, and polyenes.
  • *ERG3* mutants exhibited significantly reduced ergosterol levels (<1%), accumulation of non-toxic sterol intermediates, and increased chitin content, indicating cell membrane and cell wall remodeling.
  • These adaptations enable the pathogen to evade multiple antifungal drug classes.

Conclusions:

  • Single point mutations, particularly in *ERG3*, can rapidly drive multidrug resistance in *C. lusitaniae* through coordinated sterol and cell wall reprogramming.
  • Echinocandin monotherapy can inadvertently select for broad antifungal resistance, necessitating careful treatment strategies.
  • The findings parallel recent clinical observations and underscore the importance of surveillance for resistance evolution under echinocandin treatment.
Keywords:
Clavispora lusitaniaeERG3OSH2echinocandinmicafunginmultidrug resistance

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