Identification of the anti-mycobacterial functional properties of piperidinol derivatives

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. ISSN 0007-1188

[img]
Preview
PDF (Published_Version) - Published Version
Available under License Creative Commons Attribution.

Download (730kB) | Preview

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 M. smegmatis and Gram-negative organisms. Cytotoxicity studies were undertaken in order to determine the selectivity index for these compounds. Spontaneous resistant mutants of M. smegmatis were generated against the piperidinol and corresponding bis-Mannich base lead derivatives and whole genome sequencing employed to determine the genetic modifications that lead 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 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. LINKED ARTICLES: This article is part of a themed section on Drug Metabolism and Antibiotic Resistance in Micro-organisms. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.14/issuetoc.

Item Type: Article
Additional Information: © 2017 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.
Uncontrolled Keywords: chemical synthesis,drug effects,dose-response relationship, drug,drug effects,humans,microbial sensitivity tests,molecular structure,drug effects,chemical synthesis,drug effects,drug effects,structure-activity relationship,tumor cells, cultured
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User: LivePure Connector
Date Deposited: 04 Jan 2020 04:08
Last Modified: 30 Jun 2020 00:07
URI: https://ueaeprints.uea.ac.uk/id/eprint/73481
DOI: 10.1111/bph.13744

Actions (login required)

View Item View Item