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Screening of TB Actives for Activity against Nontuberculous Mycobacteria Delivers High Hit Rates.
Front Microbiol. 2017; 8:1539.FM

Abstract

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.

Authors+Show Affiliations

Department of Medicine, Yong Loo Lin School of Medicine, National University of SingaporeSingapore, Singapore.Department of Medicine, Yong Loo Lin School of Medicine, National University of SingaporeSingapore, Singapore.Department of Medicine, Yong Loo Lin School of Medicine, National University of SingaporeSingapore, Singapore.Medicines for Malaria VentureGeneva, Switzerland.Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of SingaporeSingapore. New Jersey Medical School, Public Health Research Institute, Rutgers, The State University of New JerseyNewark, NJ, United States.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28861054

Citation

Low, Jian Liang, et al. "Screening of TB Actives for Activity Against Nontuberculous Mycobacteria Delivers High Hit Rates." Frontiers in Microbiology, vol. 8, 2017, p. 1539.
Low JL, Wu ML, Aziz DB, et al. Screening of TB Actives for Activity against Nontuberculous Mycobacteria Delivers High Hit Rates. Frontiers in microbiology. 2017;8:1539.
Low, J. L., Wu, M. L., Aziz, D. B., Laleu, B., & Dick, T. (2017). Screening of TB Actives for Activity against Nontuberculous Mycobacteria Delivers High Hit Rates. Frontiers in Microbiology, 8, 1539. https://doi.org/10.3389/fmicb.2017.01539
Low JL, et al. Screening of TB Actives for Activity Against Nontuberculous Mycobacteria Delivers High Hit Rates. Frontiers in microbiology. 2017;8:1539. PubMed PMID: 28861054.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Screening of TB Actives for Activity against Nontuberculous Mycobacteria Delivers High Hit Rates. AU - Low,Jian Liang, AU - Wu,Mu-Lu, AU - Aziz,Dinah Binte, AU - Laleu,Benoît, AU - Dick,Thomas, Y1 - 2017/08/15/ PY - 2017/06/02/received PY - 2017/07/31/accepted PY - 2017/9/2/entrez PY - 2017/9/2/pubmed PY - 2017/9/2/medline KW - Mycobacterium abscessus KW - Mycobacterium avium KW - NTM KW - drug screening KW - pathogen box SP - 1539 EP - 1539 JF - Frontiers in microbiology VL - 8 N2 - 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. SN - 1664-302X UR - https://www.unboundmedicine.com/medline/citation/28861054/Screening_of_TB_Actives_for_Activity_against_Nontuberculous_Mycobacteria_Delivers_High_Hit_Rates_ L2 - https://doi.org/10.3389/fmicb.2017.01539 DB - PRIME DP - Unbound Medicine ER -
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