Azithromycin blocks autophagy and may predispose cystic fibrosis patients to mycobacterial infection

J Clin Invest. 2011 Sep;121(9):3554-63. doi: 10.1172/JCI46095. Epub 2011 Aug 1.

Abstract

Azithromycin is a potent macrolide antibiotic with poorly understood antiinflammatory properties. Long-term use of azithromycin in patients with chronic inflammatory lung diseases, such as cystic fibrosis (CF), results in improved outcomes. Paradoxically, a recent study reported that azithromycin use in patients with CF is associated with increased infection with nontuberculous mycobacteria (NTM). Here, we confirm that long-term azithromycin use by adults with CF is associated with the development of infection with NTM, particularly the multi-drug-resistant species Mycobacterium abscessus, and identify an underlying mechanism. We found that in primary human macrophages, concentrations of azithromycin achieved during therapeutic dosing blocked autophagosome clearance by preventing lysosomal acidification, thereby impairing autophagic and phagosomal degradation. As a consequence, azithromycin treatment inhibited intracellular killing of mycobacteria within macrophages and resulted in chronic infection with NTM in mice. Our findings emphasize the essential role for autophagy in the host response to infection with NTM, reveal why chronic use of azithromycin may predispose to mycobacterial disease, and highlight the dangers of inadvertent pharmacological blockade of autophagy in patients at risk of infection with drug-resistant pathogens.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Anti-Bacterial Agents* / adverse effects
  • Anti-Bacterial Agents* / pharmacology
  • Anti-Bacterial Agents* / therapeutic use
  • Autophagy / drug effects*
  • Azithromycin* / adverse effects
  • Azithromycin* / pharmacology
  • Azithromycin* / therapeutic use
  • COS Cells
  • Chlorocebus aethiops
  • Cystic Fibrosis / complications*
  • Cystic Fibrosis / drug therapy*
  • Cystic Fibrosis / microbiology
  • Drug Resistance, Bacterial
  • Enzyme Inhibitors / pharmacology
  • HeLa Cells
  • Humans
  • Lysosomes / metabolism
  • Macrolides / pharmacology
  • Macrophages / cytology
  • Macrophages / drug effects
  • Macrophages / microbiology
  • Mice
  • Mice, Inbred C57BL
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism
  • Mycobacterium / drug effects
  • Mycobacterium / pathogenicity
  • Mycobacterium / physiology
  • Mycobacterium Infections / etiology*
  • Mycobacterium Infections / microbiology
  • Phagosomes / drug effects
  • Phagosomes / metabolism
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Sirolimus / pharmacology

Substances

  • Anti-Bacterial Agents
  • Enzyme Inhibitors
  • Macrolides
  • Microtubule-Associated Proteins
  • Recombinant Fusion Proteins
  • light chain 3, human
  • Azithromycin
  • bafilomycin A1
  • Sirolimus