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Visible-Light-Activated Molecular Machines Kill Fungi by Necrosis Following Mitochondrial Dysfunction and Calcium

Ana L Santos1,2, Jacob L Beckham1, Dongdong Liu1

  • 1Department of Chemistry, Rice University, Houston, TX, 77005, USA.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|January 30, 2023
PubMed

Insights

New molecular machines (MMs) activated by visible light effectively kill fungi, including resistant strains and biofilms. These MMs offer a novel strategy against invasive fungal infections by targeting mitochondria and enhancing existing antifungal drugs.

Area of Science:

  • Biochemistry
  • Mycology
  • Nanotechnology

Background:

  • Invasive fungal infections pose a significant global health challenge.
  • Increasing antifungal drug resistance necessitates novel therapeutic approaches.
  • Current treatments face limitations due to toxicity and resistance development.

Purpose of the Study:

  • To investigate the efficacy of visible-light-activated molecular machines (MMs) as a novel antifungal strategy.
  • To elucidate the mechanism of action of MMs against fungal pathogens.
  • To evaluate the synergistic potential of MMs with conventional antifungals.

Main Methods:

  • Visible-light activation of synthetic molecular machines (MMs).
  • Assessment of antifungal activity against planktonic and biofilm fungal populations.
  • Mechanism-of-action studies involving mitochondrial phospholipid binding and dysfunction.
  • In vivo and ex vivo studies using a porcine model of onychomycosis.

Main Results:

  • MMs demonstrated superior efficacy against fungal populations compared to conventional antifungals.
  • No resistance development was observed with MMs.
  • MMs induce fungal cell death via mitochondrial dysfunction and calcium overload.
  • MMs synergize with existing antifungals by inhibiting efflux pumps.
  • MMs reduced fungal burden in vivo and in an ex vivo onychomycosis model.

Conclusions:

  • Visible-light-activated MMs represent a promising new class of antifungals.
  • MMs offer a resistance-proof therapeutic option for invasive fungal infections.
  • MMs enhance the efficacy of standard antifungal treatments through synergistic action.
Keywords:
antifungalfungal mitochondrial phospholipidsmolecular machinesreduction of infection-associated mortality and fungal burdenvisible light activation

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