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J Antimicrob Chemother. 2014 Jun;69(6):1599-607. doi: 10.1093/jac/dku024. Epub 2014 Feb 10.

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

Author information

1
Institute Pasteur Korea, Seongnam-si, Gyeonggi-do, Korea.
2
Department of Clinical Laboratory Science, Semyung University, Jecheon, Chungbuk, Korea.
3
Division of Analytical Bio-imaging, Chuncheon Center, Korea Basic Science Institute, Chuncheon, Gangwon-do, Korea.
4
Institute Pasteur Korea, Seongnam-si, Gyeonggi-do, Korea jang@ip-korea.org.

Abstract

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.

KEYWORDS:

Mycobacterium abscessus disease; combination therapy; drug discovery; invertebrate model

PMID:
24519481
DOI:
10.1093/jac/dku024
[Indexed for MEDLINE]

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