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

Oh, Chun-Taek; Moon, Chéol; Park, Ok Kyu; Kwon, Seung‐Hae; Jang, Jichan

doi:10.1093/jac/dku024

Cited by 40 publications

(33 citation statements)

References 22 publications

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“…New nonmammalian models of infection have been developed, including for Drosophila melanogaster (33,34), Caenorhabditis elegans (35), or Danio rerio (36,37), offering advantages in terms of speed, cost, technical convenience, and ethical acceptability over the mouse model. Except for the recent Drosophila model (34), these models have not been reported for antibiotic assessments against M. abscessus.…”

Section: Discussionmentioning

confidence: 99%

In Vivo Assessment of Drug Efficacy against Mycobacterium abscessus Using the Embryonic Zebrafish Test System

Bernut

Moigne

Lesne

et al. 2014

Antimicrob Agents Chemother

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c Mycobacterium abscessus is responsible for a wide spectrum of clinical syndromes and is one of the most intrinsically drug-resistant mycobacterial species. Recent evaluation of the in vivo therapeutic efficacy of the few potentially active antibiotics against M. abscessus was essentially performed using immunocompromised mice. Herein, we assessed the feasibility and sensitivity of fluorescence imaging for monitoring the in vivo activity of drugs against acute M. abscessus infection using zebrafish embryos. A protocol was developed where clarithromycin and imipenem were directly added to water containing fluorescent M. abscessusinfected embryos in a 96-well plate format. The status of the infection with increasing drug concentrations was visualized on a spatiotemporal level. Drug efficacy was assessed quantitatively by measuring the index of protection, the bacterial burden (CFU), and the number of abscesses through fluorescence measurements. Both drugs were active in infected embryos and were capable of significantly increasing embryo survival in a dose-dependent manner. Protection from bacterial killing correlated with restricted mycobacterial growth in the drug-treated larvae and with reduced pathophysiological symptoms, such as the number of abscesses within the brain. In conclusion, we present here a new and efficient method for testing and compare the in vivo activity of two clinically relevant drugs based on a fluorescent reporter strain in zebrafish embryos. This approach could be used for rapid determination of the in vivo drug susceptibility profile of clinical isolates and to assess the preclinical efficacy of new compounds against M. abscessus. The emerging pathogen Mycobacterium abscessus is the etiological agent of a wide spectrum of infections in humans, including severe chronic pulmonary and disseminated infections, mostly in immunosuppressed and cystic fibrosis (CF) patients (1), and cutaneous diseases, often posttraumatic and postsurgical. This neglected pathogen causes a higher fatality rate than other rapidly growing mycobacteria (RGM), and CF patient infections is becoming a major threat in most CF centers worldwide (2). M. abscessus infections occur in early childhood (3), are severe and sometimes fatal, especially following transplantation (4-6), and may lead to outbreaks of infection (6). It is also the main RGM responsible for nosocomial and iatrogenic infections in humans (postinjection abscesses, cardiac surgery, and plastic surgery) (7-9). It has been reported to cross the blood-brain barrier and cause important central nervous system (CNS) lesions. Although a rapid grower, M. abscessus possesses several important pathogenic traits, such as the ability to (i) persist silently for years and even decades in the human host (10) and to (ii) induce lung disease with caseous lesions and granuloma formation in the parenchyma (11, 12).The major issue with M. abscessus relies on its intrinsic resistance to the most available antibiotics. The American Thoracic Society has recommended different...

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Section: Discussionmentioning

confidence: 99%

In Vivo Assessment of Drug Efficacy against Mycobacterium abscessus Using the Embryonic Zebrafish Test System

Bernut

Moigne

Lesne

et al. 2014

Antimicrob Agents Chemother

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“…However, in the past few years the development of multiple cellular, non-mammalian and mammalian models have helped to study the chronology and the pathology of Mabs infection (Byrd and Lyons, 1999; Howard et al, 2006; Ordway et al, 2008; Oh et al, 2013; Bernut et al, 2014a; Bakala N'Goma et al, 2015; Roux et al, 2016). Among these new model systems, a few have been validated for their suitability for in vivo drug efficacy studies against Mabs (Ordway et al, 2008; Lerat et al, 2014; Oh et al, 2014; Bernut et al, 2014b). These different infection models and their applications are discussed below in more details.…”

Section: Introductionmentioning

confidence: 99%

The Diverse Cellular and Animal Models to Decipher the Physiopathological Traits of Mycobacterium abscessus Infection

Bernut

Herrmann

Ordway

et al. 2017

Front. Cell. Infect. Microbiol.

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Mycobacterium abscessus represents an important respiratory pathogen among the rapidly-growing non-tuberculous mycobacteria. Infections caused by M. abscessus are increasingly found in cystic fibrosis (CF) patients and are often refractory to antibiotic therapy. The underlying immunopathological mechanisms of pathogenesis remain largely unknown. A major reason for the poor advances in M. abscessus research has been a lack of adequate models to study the acute and chronic stages of the disease leading to delayed progress of evaluation of therapeutic efficacy of potentially active antibiotics. However, the recent development of cellular models led to new insights in the interplay between M. abscessus with host macrophages as well as with amoebae, proposed to represent the environmental host and reservoir for non-tuberculous mycobacteria. The zebrafish embryo has also appeared as a useful alternative to more traditional models as it recapitulates the vertebrate immune system and, due to its optical transparency, allows a spatio-temporal visualization of the infection process in a living animal. More sophisticated immunocompromised mice have also been exploited recently to dissect the immune and inflammatory responses to M. abscessus. Herein, we will discuss the limitations, advantages and potential offered by these various models to study the pathophysiology of M. abscessus infection and to assess the preclinical efficacy of compounds active against this emerging human pathogen.

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“…Regarding M. abscessus infection, in vitro DST studies demonstrated a low MIC of CFZ and in vitro synergy between CFZ and other antibiotics, such as clarithromycin (CLR), AMK, or tigecycline (23)(24)(25)(26)(27)(28). The antimycobacterial activity of CFZ against M. abscessus was also demonstrated in vivo with Drosophila melanogaster and mouse models of infection (29,30).…”

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confidence: 97%

Clofazimine-Containing Regimen for the Treatment of Mycobacterium abscessus Lung Disease

Yang

Jhun

Moon

et al. 2017

Antimicrob Agents Chemother

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Patients with lung disease caused by Mycobacterium abscessus subsp. abscessus (here M. abscessus) typically have poor treatment outcomes. Although clofazimine (CFZ) has been increasingly used in the treatment of M. abscessus lung disease in clinical practice, there are no reported data on its effectiveness for this disease. This study sought to evaluate the clinical efficacy of a CFZ-containing regimen for the treatment of M. abscessus lung disease. We performed a retrospective review of the medical records of 42 patients with M. abscessus lung disease who were treated with CFZ-containing regimens between November 2013 and January 2015. CFZ was administered in combination with other antibiotics as an initial antibiotic regimen in 15 (36%) patients (initial treatment group), and it was added to an existing antibiotic regimen for refractory M. abscessus lung disease in 27 (64%) patients (salvage treatment group). Overall, there was an 81% treatment response rate based on symptoms and a 31% response rate based on radiographic findings. Conversion to culture-negative sputum samples was achieved in 10 (24%) patients after CFZ-containing antibiotic treatment, and during treatment, there were significant decreases in the positivity of semiquantitative sputum cultures for acid-fast bacilli in both the initial (P ϭ 0.018) and salvage (P ϭ 0.001) treatment groups. Our study suggests that CFZ-containing regimens may improve treatment outcomes in patients with M. abscessus lung disease and that a prospective evaluation of CFZ in M. abscessus lung disease is warranted.

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

Cited by 40 publications

References 22 publications

In Vivo Assessment of Drug Efficacy against Mycobacterium abscessus Using the Embryonic Zebrafish Test System

In Vivo Assessment of Drug Efficacy against Mycobacterium abscessus Using the Embryonic Zebrafish Test System

The Diverse Cellular and Animal Models to Decipher the Physiopathological Traits of Mycobacterium abscessus Infection

Clofazimine-Containing Regimen for the Treatment of Mycobacterium abscessus Lung Disease

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