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Fragment-Based Whole Cell Screen Delivers Hits against M. tuberculosis and Non-tuberculous Mycobacteria.
Front Microbiol. 2016; 7:1392.FM

Abstract

Reactive multi-target 'fragment drugs' represent critical components of current tuberculosis regimens. These compounds, such as pyrazinamide, are old synthetic antimycobacterials that are activated inside Mycobacterium tuberculosis bacilli and are smaller than the usual drug-like, single-target molecules. Based on the success of small 'dirty' drugs in the chemotherapy of tuberculosis, we suggested previously that fragment-based whole cell screens should be introduced in our current antimycobacterial drug discovery efforts. Here, we carried out such a screen and characterized bactericidal activity, selectivity and spectrum of hits we obtained. A library of 1725 fragments was tested at a single concentration for growth inhibitory activity against M. bovis BCG as screening strain and 38 of 116 primary hits were confirmed in dose response analyses to be active against virulent M. tuberculosis. Bacterial kill experiments showed that most hits displayed bactericidal activity at their minimal inhibitory concentration. Cytotoxicity assays established that a large proportion of hits displayed a favorable selectivity index for mammalian cells. Importantly, one third of M. tuberculosis active fragments were also active against M. abscessus and M. avium, two emerging non-tuberculous mycobacterial (NTM) pathogens, opening the opportunity to develop broad spectrum antimycobacterials. Activity determination against Gram positive (Staphylococcus aureus) and Gram negative (Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa) bacteria, as well as fungi (Candida albicans, Cryptococcus neoformans) showed only a small overlap indicating a generally narrow spectrum of these novel antimicrobial hits for mycobacteria. In conclusion, we carried out the first fragment-based whole cell screen against bacteria and identified a substantial number of hits with excellent physicochemical properties and dual activity against M. tuberculosis and NTM pathogens. These hits will now be evaluated in animal models of mycobacterial infection to determine whether any of them can be moved forward as a new antimycobacterial fragment drug candidate.

Authors+Show Affiliations

Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore Singapore, Singapore.Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore Singapore, Singapore.Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore Singapore, Singapore.Department of Pharmacy, National University of SingaporeSingapore, Singapore; Centre for Life Sciences, Life Sciences Institute, National University of SingaporeSingapore, Singapore.Department of Pharmacy, National University of Singapore Singapore, Singapore.Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of SingaporeSingapore, Singapore; BSL3 Core Facility, Centre for Translational Medicine, Yong Loo Lin School of Medicine, National University of SingaporeSingapore, Singapore.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27656168

Citation

Moreira, Wilfried, et al. "Fragment-Based Whole Cell Screen Delivers Hits Against M. Tuberculosis and Non-tuberculous Mycobacteria." Frontiers in Microbiology, vol. 7, 2016, p. 1392.
Moreira W, Lim JJ, Yeo SY, et al. Fragment-Based Whole Cell Screen Delivers Hits against M. tuberculosis and Non-tuberculous Mycobacteria. Frontiers in microbiology. 2016;7:1392.
Moreira, W., Lim, J. J., Yeo, S. Y., Ramanujulu, P. M., Dymock, B. W., & Dick, T. (2016). Fragment-Based Whole Cell Screen Delivers Hits against M. tuberculosis and Non-tuberculous Mycobacteria. Frontiers in Microbiology, 7, 1392. https://doi.org/10.3389/fmicb.2016.01392
Moreira W, et al. Fragment-Based Whole Cell Screen Delivers Hits Against M. Tuberculosis and Non-tuberculous Mycobacteria. Frontiers in microbiology. 2016;7:1392. PubMed PMID: 27656168.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Fragment-Based Whole Cell Screen Delivers Hits against M. tuberculosis and Non-tuberculous Mycobacteria. AU - Moreira,Wilfried, AU - Lim,Jia Jie, AU - Yeo,Si Ying, AU - Ramanujulu,Pondy M, AU - Dymock,Brian W, AU - Dick,Thomas, Y1 - 2016/09/07/ PY - 2016/03/11/received PY - 2016/08/23/accepted PY - 2016/9/23/entrez PY - 2016/9/23/pubmed PY - 2016/9/23/medline KW - M. abscessus KW - M. avium KW - NTM KW - fragments KW - poly-pharmacology KW - tuberculosis SP - 1392 EP - 1392 JF - Frontiers in microbiology VL - 7 N2 - Reactive multi-target 'fragment drugs' represent critical components of current tuberculosis regimens. These compounds, such as pyrazinamide, are old synthetic antimycobacterials that are activated inside Mycobacterium tuberculosis bacilli and are smaller than the usual drug-like, single-target molecules. Based on the success of small 'dirty' drugs in the chemotherapy of tuberculosis, we suggested previously that fragment-based whole cell screens should be introduced in our current antimycobacterial drug discovery efforts. Here, we carried out such a screen and characterized bactericidal activity, selectivity and spectrum of hits we obtained. A library of 1725 fragments was tested at a single concentration for growth inhibitory activity against M. bovis BCG as screening strain and 38 of 116 primary hits were confirmed in dose response analyses to be active against virulent M. tuberculosis. Bacterial kill experiments showed that most hits displayed bactericidal activity at their minimal inhibitory concentration. Cytotoxicity assays established that a large proportion of hits displayed a favorable selectivity index for mammalian cells. Importantly, one third of M. tuberculosis active fragments were also active against M. abscessus and M. avium, two emerging non-tuberculous mycobacterial (NTM) pathogens, opening the opportunity to develop broad spectrum antimycobacterials. Activity determination against Gram positive (Staphylococcus aureus) and Gram negative (Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa) bacteria, as well as fungi (Candida albicans, Cryptococcus neoformans) showed only a small overlap indicating a generally narrow spectrum of these novel antimicrobial hits for mycobacteria. In conclusion, we carried out the first fragment-based whole cell screen against bacteria and identified a substantial number of hits with excellent physicochemical properties and dual activity against M. tuberculosis and NTM pathogens. These hits will now be evaluated in animal models of mycobacterial infection to determine whether any of them can be moved forward as a new antimycobacterial fragment drug candidate. SN - 1664-302X UR - https://www.unboundmedicine.com/medline/citation/27656168/Fragment_Based_Whole_Cell_Screen_Delivers_Hits_against_M__tuberculosis_and_Non_tuberculous_Mycobacteria_ L2 - https://doi.org/10.3389/fmicb.2016.01392 DB - PRIME DP - Unbound Medicine ER -
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