Novel drug combination for Mycobacterium abscessus disease therapy identified in a Drosophila infection model

• Published in: Journal of antimicrobial chemotherapy 2014-06, Vol.69 (6), p.1599-1607
• Main Authors: Oh, Chun-Taek, Moon, Cheol, Park, Ok Kyu, Kwon, Seung-Hae, Jang, Jichan
• Format: Article
• Language: English
• Subjects: Animals; Anti-Bacterial Agents - pharmacology; Anti-Bacterial Agents - therapeutic use; Antibiotics; Bacteria; Bacterial Load - drug effects; Disease Models, Animal; Drosophila; Drug Evaluation, Preclinical; Drug therapy; Drug Therapy, Combination; Female; Gene Expression; Genes, Reporter; Insects; Mycobacterium; Mycobacterium - drug effects; Mycobacterium - genetics; Mycobacterium abscessus; Mycobacterium Infections - drug therapy; Mycobacterium Infections - microbiology; Mycobacterium Infections - mortality
• ISSN: 0305-7453; 1460-2091
• DOI: 10.1093/jac/dku024

Objectives Mycobacterium abscessus is known to be the most drug-resistant Mycobacterium and accounts for ∼80% of pulmonary infections caused by rapidly growing mycobacteria. This study reports a new Drosophila melanogaster–M. abscessus infection model that can be used as an in vivo efficacy model for anti-M. abscessus drug potency assessment. Methods D. melanogaster were challenged with M. abscessus, and infected flies were fed with a fly medium containing tigecycline, clarithromycin, linezolid, clofazimine, moxifloxacin, amikacin, cefoxitin, dinitrobenzamide or metronidazole at different concentrations (0, 100 and 500 mg/L). The survival rates of infected flies were plotted and bacterial colonization/dissemination in fly bodies was monitored by cfu determination and green fluorescent protein epifluorescence. Results The D. melanogaster–M. abscessus model enabled an assessment of the effectiveness of antibiotic treatment. Tigecycline was the best drug for extending the lifespan of M. abscessus-infected Drosophila, followed by clarithromycin and linezolid. Several different combinations of tigecycline, linezolid and clarithromycin were tested to determine the best combination. Tigecycline (25 mg/L) plus linezolid (500 mg/L) was the best drug combination and its efficacy was superior to conventional regimens, not only in prolonging infected fly survival but also against M. abscessus colonization and dissemination. Conclusions This D. melanogaster–M. abscessus infection/curing methodology may be useful for the rapid evaluation of potential drug candidates. In addition, new combinations using tigecycline and linezolid should be considered as possible next-generation combination therapies to be assessed in higher organisms.