JVA, an isoniazid analogue, is a bioactive compound against a clinical isolate of the Mycobacterium avium complex

• Published in: Tuberculosis (Edinburgh, Scotland) Vol. 115; pp. 108 - 112
• Main Authors: Fahel, Júlia S., Vieira, Rafael P., Marinho, Fábio V., Santos, Viviane C., de Assis, João Vitor, Corsetti, Patrícia P., Ferreira, Rafaela S., de Almeida, Mauro V., Oliveira, Sergio C.
• Format: Journal Article
• Language: English
• Published: Scotland Elsevier Ltd 01.03.2019; Elsevier Science Ltd
• Subjects: Adenine; Analysis of Variance; Animals; Antibiotic resistance; Antibiotics; Antitubercular Agents - pharmacology; Bioactive compounds; Biological membranes; Clarithromycin; Ethambutol; Hydrazones - pharmacology; Isoniazid; Isoniazid - analogs & derivatives; Isoniazid analogue; Macrophage; Macrophages; Macrophages - microbiology; Membranes; Mice, Inbred C57BL; Microbial Sensitivity Tests; Mycobacterium avium; Mycobacterium avium complex; Mycobacterium avium Complex - drug effects; Mycobacterium avium Complex - growth & development; Mycobacterium avium-intracellulare Infection - drug therapy; NAD; Nicotinamide; Nicotinamide adenine dinucleotide; Pathogenicity; Pathogens; pH effects; Phagosomes; Rifabutin; Side effects; Mycobacterium avium complex; Isoniazid analogue; Macrophage
• ISSN: 1472-9792; 1873-281X
• DOI: 10.1016/j.tube.2019.03.002

Bacteria belonging to Mycobacterium avium complex are organisms of low pathogenicity that infect immunosuppressed individuals. Infection is treated with an antimicrobial macrolide, Clarithromycin (CAM) or Azitromycin, associated with Ethambutol and Rifabutin during 12 months. Regimen long duration and side effects hinder patient's commitment to treatment favoring emergence of antibiotic resistance. In this present study, we evaluated the activity of JVA, an Isoniazid (INH) derivative, against M. avium 2447, a clinical isolate. We demonstrated that JVA reduces M. avium 2447 growth in macrophages, more efficiently than CAM and INH. In order to explore JVA mechanism of action, we investigated compound properties and performed pH-dependent stability studies. Our results suggest an enhanced ability of JVA to cross biological membranes. Furthermore, we suggest that in acidic conditions of macrophages' phagosomes, where mycobacteria replicate, JVA would be promptly hydrolyzed to INH, delivering the adduct INH-nicotinamide adenine dinucleotide and thus inhibiting M. avium 2447 growth.