A broad-spectrum antibiotic, DCAP, reduces uropathogenic Escherichia coli infection and enhances vorinostat anticancer activity by modulating autophagy

Cell Death Dis. 2018 Jul 13;9(7):780. doi: 10.1038/s41419-018-0786-4.

Abstract

The cellular recycling pathway of autophagy plays a fundamental role in adaptive responses to nutrient deprivation and other forms of stress under physiological and pathological conditions. However, autophagy can also be a double-edge sword during certain bacterial infections (such as urinary tract infections) and in cancer, where it can be hijacked by the pathogens and cancer cells, respectively, to promote their own survival. Thus, autophagy modulation can potentially have multiple effects in multiple contexts and this property can be leveraged to improve outcomes. In this report, we identify that a broad-spectrum antibiotic, 2-((3-(3, 6-dichloro-9H-carbazol-9-yl)-2-hydroxypropyl) amino)-2-(hydroxymethyl) propane-1, 3-diol (DCAP) modulates autophagy. We employed combined biochemical, fluorescence microscopy and correlative light electron microscopy approaches to demonstrate that DCAP treatment blocks autophagy at the late stages by preventing autophagolysosome maturation and interrupting the autophagic flux. We further show that, DCAP significantly reduces UPEC infection in urinary tract epithelial cells via inhibition of autophagy. Finally, we reveal that DCAP enhances the anticancer activity of the histone acetyltransferase (HDAC) inhibitor, vorinostat, which has been reported to increase susceptibility to bacterial infections as a common adverse effect. Collectively, our data support the concept that DCAP represents a valuable chemical scaffold for the development of an innovative class of bactericidal autophagy inhibitors for treatment of urinary tract infections and/or for adjuvant therapy in cancer treatment.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminophenols / pharmacology*
  • Anti-Bacterial Agents / pharmacology
  • Anti-Bacterial Agents / therapeutic use*
  • Antineoplastic Agents / pharmacology*
  • Autophagosomes / drug effects
  • Autophagosomes / metabolism
  • Autophagosomes / ultrastructure
  • Autophagy / drug effects*
  • Cell Line, Tumor
  • Escherichia coli Infections / drug therapy*
  • Escherichia coli Infections / microbiology
  • Histone Deacetylase Inhibitors / pharmacology
  • Humans
  • Intracellular Membranes / drug effects
  • Intracellular Membranes / metabolism
  • Lysosomes / drug effects
  • Lysosomes / metabolism
  • Lysosomes / ultrastructure
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Urinary Tract Infections / drug therapy*
  • Urinary Tract Infections / microbiology
  • Uropathogenic Escherichia coli / drug effects
  • Uropathogenic Escherichia coli / physiology*
  • Vorinostat / pharmacology*

Substances

  • Aminophenols
  • Anti-Bacterial Agents
  • Antineoplastic Agents
  • Histone Deacetylase Inhibitors
  • 3,5-dichloro-1,4-aminophenol
  • Vorinostat