Understanding nontuberculous mycobacterial lung disease: it’s been a long time coming

Griffith, David E.; Aksamit, Timothy R.

doi:10.12688/f1000research.9272.1

Cited by 41 publications

(38 citation statements)

References 62 publications

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“…Over past decades increasing rates of human disease secondary to NTMs have been reported [112,113,114]. NTMs could affect multiple organs, but pulmonary disease is the most common reason for clinical symptoms as a result of NTM inhalation.…”

Section: Non-tuberculous Mycobacteriamentioning

confidence: 99%

Inhaled Antibiotic Therapy in Chronic Respiratory Diseases

Maselli

Keyt

Restrepo

2017

IJMS

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The management of patients with chronic respiratory diseases affected by difficult to treat infections has become a challenge in clinical practice. Conditions such as cystic fibrosis (CF) and non-CF bronchiectasis require extensive treatment strategies to deal with multidrug resistant pathogens that include Pseudomonas aeruginosa, Methicillin-resistant Staphylococcus aureus, Burkholderia species and non-tuberculous Mycobacteria (NTM). These challenges prompted scientists to deliver antimicrobial agents through the pulmonary system by using inhaled, aerosolized or nebulized antibiotics. Subsequent research advances focused on the development of antibiotic agents able to achieve high tissue concentrations capable of reducing the bacterial load of difficult-to-treat organisms in hosts with chronic respiratory conditions. In this review, we focus on the evidence regarding the use of antibiotic therapies administered through the respiratory system via inhalation, nebulization or aerosolization, specifically in patients with chronic respiratory diseases that include CF, non-CF bronchiectasis and NTM. However, further research is required to address the potential benefits, mechanisms of action and applications of inhaled antibiotics for the management of difficult-to-treat infections in patients with chronic respiratory diseases.

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Section: Non-tuberculous Mycobacteriamentioning

confidence: 99%

Inhaled Antibiotic Therapy in Chronic Respiratory Diseases

Maselli

Keyt

Restrepo

2017

IJMS

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“…Nontuberculous mycobacteria (NTM)—relatives of the tuberculosis (TB) causative agent Mycobacterium tuberculosis , have recently emerged as a new threat to humans (Griffith and Aksamit, 2016 ; Stout et al, 2016 ). These bacteria can cause a wide range of illnesses, including TB-like pulmonary disease, which are difficult to cure (Griffith et al, 2007 ; Griffith, 2010 ).…”

Section: Introductionmentioning

confidence: 99%

“…In comparison with TB, the NTM drug pipeline is remarkably empty, calling for an urgent need to develop anti-NTM drugs (Griffith and Aksamit, 2016 ; Raju et al, 2016 ). The fact that NTM are in general resistant to most anti-tubercular drugs suggests a drug susceptibility profile distinct from M. tuberculosis (Pang et al, 2015 ; Cowman et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

Screening of TB Actives for Activity against Nontuberculous Mycobacteria Delivers High Hit Rates

Low

Aziz

et al. 2017

Front. Microbiol.

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The prevalence of lung disease due to infections with nontuberculous mycobacteria (NTM) has been increasing and surpassed tuberculosis (TB) in some countries. Treatment outcomes are often unsatisfactory, highlighting an urgent need for new anti-NTM medications. Although NTM in general do not respond well to TB specific drugs, the similarities between NTM and Mycobacterium tuberculosis at the molecular and cell structural level suggest that compound libraries active against TB could be leveraged for NTM drug discovery. Here we tested this hypothesis. The Pathogen Box from the Medicines for Malaria Venture (MMV) is a collection of 400 diverse drug-like compounds, among which 129 are known to be active against M. tuberculosis. By screening this compound collection against two NTM species, Mycobacterium abscessus and Mycobacterium avium, we showed that indeed the hit rates for NTM among TB active compounds is significantly higher compared to compounds that are not active against TB. MIC/dose response confirmation identified 10 top hits. Bactericidal activity determination demonstrated attractive potency for a subset of the confirmed hits. In vivo pharmacokinetic profiling showed that some of the compounds present reasonable starting points for medicinal chemistry programs. Three of the top hits were oxazolidinones, suggesting the potential for repositioning this class of protein synthesis inhibitors to replace linezolid which suffers from low potency. Two hits were inhibitors of the trehalose monomycolate transporter MmpL3, suggesting that this transmembrane protein may be an attractive target for NTM. Other hits are predicted to target a range of functions, including cell division (FtsZ), DNA gyrase (GyrB), dihydrofolate reductase, RNA polymerase and ABC transporters. In conclusion, our study showed that screening TB active compounds for activity against NTM resulted in high hit rates, suggesting that this may be an attractive approach to kick start NTM drug discovery projects. In addition, the work identified a series of novel high value NTM hits with associated candidate targets which can be followed up in hit-to-lead projects for the discovery of new NTM antibiotics.

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“…Mycobacterium abscessus is a pathogenic nontuberculous mycobacteria (NTM) species and the most common cause of rapidly growing mycobacterial lung infection worldwide in patients with chronic inflammatory lung diseases such as cystic fibrosis (CF), non-CF bronchiectasis and chronic obstructive pulmonary disease (COPD) [1,2]. Antibiotic therapy often fails to achieve complete eradication and no combination drug regimen reliably cures M. abscessus lung infection at this time [3,4]. Therefore, there is an unmet need for the development of novel anti-NTM therapies.…”

Section: Introductionmentioning

confidence: 99%

Antibacterial activity of high-dose nitric oxide against pulmonary Mycobacterium abscessus disease

Bogdanovski

Chau

Robinson

et al. 2020

Access Microbiology

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Introduction. Mycobacterium abscessus is an emerging pulmonary pathogen with limited treatment options. Nitric oxide (NO) demonstrates antibacterial activity against various bacterial species, including mycobacteria. In this study, we evaluated the effect of adjunctive inhaled NO therapy, using a novel NO generator, in a CF patient with pulmonary M. abscessus disease, and examined heterogeneity of response to NO in vitro. Methods. In the compassionate-use treatment, a 24-year-old CF patient with pulmonary M. abscessus was treated with two courses of adjunctive intermittent NO, first at 160 p.p.m. for 21 days and subsequently by escalating the dose up to 240 p.p.m. for 8 days. Methemoglobin, pulmonary function, 6 min walk distance (6MWD), qualify of life and sputum microbiology were assessed. In vitro susceptibility tests were performed against patient’s isolate and comparison clinical isolates and quantified by Hill’s slopes calculated from time–kill curves. Results. M. abscessus lung infection eradication was not achieved, but improvements in selected qualify of life domains, lung function and 6MWD were observed during the study. Inhaled NO was well tolerated at 160 p.p.m. Dosing at 240 p.p.m. was stopped due to adverse symptoms, although methemoglobin levels remained within safety thresholds. In vitro susceptibility tests showed a dose-dependent NO effect on M. abscessus susceptibility and significant heterogeneity in response between M. abscessus clinical isolates. The patient’s isolate was found to be the least susceptible strain in vitro. Conclusion. These results demonstrate heterogeneity in M. abscessus susceptibility to NO and suggest that longer treatment regimens could be required to see the reduction or eradication of more resistant pulmonary strains.

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Understanding nontuberculous mycobacterial lung disease: it’s been a long time coming

Cited by 41 publications

References 62 publications

Inhaled Antibiotic Therapy in Chronic Respiratory Diseases

Inhaled Antibiotic Therapy in Chronic Respiratory Diseases

Screening of TB Actives for Activity against Nontuberculous Mycobacteria Delivers High Hit Rates

Antibacterial activity of high-dose nitric oxide against pulmonary Mycobacterium abscessus disease

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