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Identification of the anti-mycobacterial functional properties of piperidinol derivatives

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Guy, Collette S., Tichauer, Esther, Kay, Gemma L., Phillips, Daniel J., Bailey, Trisha L., Harrison, James, Furze, Christopher M., Millard, Andrew D., Gibson, Matthew I., Pallen, Mark J. and Fullam, Elizabeth (2017) Identification of the anti-mycobacterial functional properties of piperidinol derivatives. British Journal of Pharmacology, 174 (14). pp. 2183-2193. doi:10.1111/bph.13744 ISSN 1476-5381.

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Official URL: http://dx.doi.org/10.1111/bph.13744

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Abstract

Background and purpose:
Tuberculosis (TB) remains a major global health threat and is now the leading cause of death from a single infectious agent worldwide. The current TB drug regimen is inadequate and new anti-tubercular agents are urgently required to be able to successfully combat the increasing prevalence of drug-resistant TB. The purpose of this study was to investigate a piperidinol compound derivative that is highly active against the Mycobacterium tuberculosis bacillus.

Experimental approach:
The antibacterial properties of the piperidinol compound and its corresponding bis-Mannich base analogue were evaluated against Mycobacterium smegmatis and Gram-negative organisms. Cytotoxicity studies were undertaken in order to determine the selectivity index for these compounds. Spontaneous resistant mutants of Mycobacterium smegmatis were generated against the piperidinol and corresponding bis-Mannich base lead derivatives and whole genome sequencing employed to determine genetic modifications as result to selection pressure in the presence of these compounds.

Key results:
The piperidinol and the bis-Mannich base analogue were found to be selective for mycobacteria and rapidly kill this organism with a cytotoxicity selectivity index for mycobacteria of >30 fold. Whole genome sequencing of M. smegmatis strains resistant to the lead compounds led to the identification of a number of single nucleotide polymorphisms (SNPs) indicating multiple-targets.

Conclusion and implications:
Our results indicate that the piperidinol moiety represents an attractive compound class in the pursuit of novel anti-tubercular agents.

Item Type: Journal Article
Subjects: R Medicine > RC Internal medicine
Divisions: Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences
Faculty of Science, Engineering and Medicine > Science > Chemistry
Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- )
Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences > Microbiology & Infection
Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School
Library of Congress Subject Headings (LCSH): Multidrug-resistant tuberculosis, Tuberculosis -- Treatment, Mycobacterium tuberculosis
Journal or Publication Title: British Journal of Pharmacology
Publisher: John Wiley & Sons Ltd.
ISSN: 1476-5381
Official Date: July 2017
Dates:
DateEvent
July 2017Published
23 March 2017Available
10 February 2017Accepted
15 June 2016Submitted
Volume: 174
Number: 14
Page Range: pp. 2183-2193
DOI: 10.1111/bph.13744
Status: Peer Reviewed
Publication Status: Published
Access rights to Published version: Restricted or Subscription Access
Date of first compliant deposit: 21 February 2017
Date of first compliant Open Access: 7 April 2017
Funder: Wellcome Trust, Royal Society (Great Britain), Research Councils UK (RCUK), European Research Council (ERC), University of Warwick. Institute of Advanced Study (IAS), Engineering and Physical Sciences Research Council (EPSRC)
Grant number: 104193/Z/14/Z (Wellcome Trust) (Royal Society (Great Britain)), MR/N006917/1 (RCUK), 638661 (ERC), RG120405 Royal Society (Great Britain), EP/M027503/1 (EPSRC)

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