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Bio-energetics Investigation of Candida albicans Using Real-time Extracellular Flux Analysis
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Inhibiting mitochondrial phosphate transport as an unexploited antifungal strategy

Catherine A McLellan1,2, Benjamin M Vincent1,3, Norma V Solis4

  • 1Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA.

Nature Chemical Biology
|December 12, 2017
PubMed

Insights

Researchers identified ML316, a novel antifungal drug, that targets the fungal mitochondrial phosphate carrier Mir1. This discovery offers a promising new strategy against drug-resistant Candida infections.

Area of Science:

  • Biochemistry
  • Mycology
  • Pharmacology

Background:

  • Developing effective antifungal therapies is challenging due to the evolutionary similarity between fungi and humans.
  • Fungal mitochondrial function is a potential therapeutic target, influencing morphogenesis, virulence, and drug resistance.

Purpose of the Study:

  • To characterize the antifungal compound ML316 and its mechanism of action.
  • To evaluate ML316 as a potential therapeutic agent against drug-resistant fungal infections.

Main Methods:

  • Mechanistic characterization using genetic, biochemical, and metabolomic approaches.
  • In vitro studies on drug-resistant Candida species.
  • In vivo studies using a mouse model of oropharyngeal candidiasis.

Main Results:

  • ML316 selectively inhibits the fungal mitochondrial phosphate carrier Mir1 at nanomolar concentrations.
  • ML316 causes metabolic catastrophe in yeast by inhibiting Mir1, leading to citrate accumulation and cell death.
  • ML316 reduces fungal burden and enhances azole efficacy in a mouse model of candidiasis.

Conclusions:

  • ML316 is the first identified inhibitor of Mir1.
  • Targeting Mir1 presents a novel therapeutic strategy for combating drug-resistant fungal infections.
  • ML316 demonstrates potential as a new antifungal therapeutic.

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