title: Azithromycin blocks autophagy and may predispose cystic fibrosis patients to mycobacterial infection.
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.
authors.affiliation: Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Renna
authors.forename: Catherine
authors.initials: C
authors.lastname: Schaffner
authors.forename: Karen
authors.initials: K
authors.lastname: Brown
authors.forename: Shaobin
authors.initials: S
authors.lastname: Shang
authors.forename: Marcela Henao
authors.initials: MH
authors.lastname: Tamayo
authors.forename: Krisztina
authors.initials: K
authors.lastname: Hegyi
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Grimsey
authors.forename: David
authors.initials: D
authors.lastname: Cusens
authors.forename: Sarah
authors.initials: S
authors.lastname: Coulter
authors.forename: Jason
authors.initials: J
authors.lastname: Cooper
authors.forename: Anne R
authors.initials: AR
authors.lastname: Bowden
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Newton
authors.forename: Beate
authors.initials: B
authors.lastname: Kampmann
authors.forename: Jennifer
authors.initials: J
authors.lastname: Helm
authors.forename: Andrew
authors.initials: A
authors.lastname: Jones
authors.forename: Charles S
authors.initials: CS
authors.lastname: Haworth
authors.forename: Randall J
authors.initials: RJ
authors.lastname: Basaraba
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: DeGroote
authors.forename: Diane J
authors.initials: DJ
authors.lastname: Ordway
authors.forename: David C
authors.initials: DC
authors.lastname: Rubinsztein
authors.forename: R Andres
authors.initials: RA
authors.lastname: Floto
mesh_terms: D000328:Adult; D000818:Animals; D000900:Anti-Bacterial Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D001343:Autophagy / Q000187:drug effects*; D017963:Azithromycin / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D019556:COS Cells; D002522:Chlorocebus aethiops; D003550:Cystic Fibrosis / Q000150:complications* / Q000188:drug therapy* / Q000382:microbiology; D024881:Drug Resistance, Bacterial; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D018942:Macrolides / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D009161:Mycobacterium / Q000187:drug effects / Q000472:pathogenicity / Q000502:physiology; D009164:Mycobacterium Infections / Q000209:etiology* / Q000382:microbiology; D010588:Phagosomes / Q000187:drug effects / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; C477012:MAP1LC3A protein, human; D018942:Macrolides; D008869:Microtubule-Associated Proteins; D011993:Recombinant Fusion Proteins; D017963:Azithromycin; C040929:bafilomycin A1; D020123:Sirolimus