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

作者：Renna Maurizio; Schaffner Catherine; Brown Karen; Shang Shaobin; Tamayo Marcela Henao; Hegyi Krisztina; Grimsey Neil J; Cusens David; Coulter Sarah; Cooper Jason; Bowden Anne R; Newton Sandra M; Kampmann Beate; Helm Jennifer; Jones Andrew; Haworth Charles S; Basaraba Randall J; DeGroote Mary Ann; Ordway Diane J; Rubinsztein David C; Floto R Andres^*

来源：Journal of Clinical Investigation, 2011, 121(9): 3554-3563.

DOI：10.1172/JCI46095

Azithromycin is a potent macrolide antibiotic with poorly understood antiinflammatory properties. Longterm 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.

• 出版日期2011-9
• 单位河北医科大学