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Thiopeptides Induce Proteasome-Independent Activation of Cellular Mitophagy

Kelly E Bird1, Christian Xander2, Sebastian Murcia2

  • 1Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599, United States.

ACS Chemical Biology
|June 27, 2020
PubMed

Insights

Thiopeptide antibiotics show promise against Mycobacterium tuberculosis. These compounds induce mitophagy, a selective removal of mitochondria, but this process does not directly aid in controlling intracellular bacterial infections.

Area of Science:

  • Microbiology
  • Immunology
  • Pharmacology

Background:

  • Thiopeptide antibiotics possess potent antibacterial activity against intracellular pathogens like Mycobacterium tuberculosis (Mtb).
  • Thiostrepton (TSR), a thiopeptide, can induce autophagy in infected macrophages, suggesting potential for host-directed therapies.
  • Understanding the host-directed effects of diverse thiopeptides is crucial for developing novel therapeutics.

Purpose of the Study:

  • To investigate the host-directed effects of various natural thiopeptides and analogs.
  • To determine if thiopeptides induce mitophagy and its relationship with antibacterial activity.
  • To assess the therapeutic potential of thiopeptides against intracellular Mtb.

Main Methods:

  • Screening of natural thiopeptides and analogs for host-directed effects.
  • Assessing mitophagy induction via selective autophagic removal of mitochondria.
  • Evaluating antibacterial activity against intracellular Mtb in macrophage models.

Main Results:

  • Thiopeptides as a class induce mitophagy, independent of proteasome inhibition or antibiotic activity.
  • Many tested thiopeptides demonstrated potent activity against intracellular Mtb.
  • Thiopeptide-induced mitophagy occurs independently of pathogen-containing autophagosomes and does not contribute to Mtb control.

Conclusions:

  • Thiopeptides induce mitophagy, expanding our understanding of their biological activities.
  • The mitophagy pathway does not directly contribute to the control of intracellular Mtb by thiopeptides.
  • These findings offer guidance for developing new thiopeptide antibiotics and host-directed therapies.

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