Identification of the anti-mycobacterial functional properties of piperidinol derivatives

Collette S Guy, Esther Tichauer, Gemma L Kay, Daniel J Phillips, Trisha L Bailey, James Harrison, Christopher M Furze, Andrew D Millard, Matthew I Gibson, Mark J Pallen, Elizabeth Fullam

Research output: Contribution to journalArticle

9 Citations (Scopus)
11 Downloads (Pure)

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.

Original languageEnglish
Pages (from-to)2183-2193
Number of pages11
JournalBritish Journal of Pharmacology
Volume174
Issue number14
Early online date14 Feb 2017
DOIs
Publication statusPublished - Jul 2017

Keywords

  • Anti-Bacterial Agents/chemical synthesis
  • Cell Survival/drug effects
  • Dose-Response Relationship, Drug
  • Escherichia coli/drug effects
  • Humans
  • Microbial Sensitivity Tests
  • Molecular Structure
  • Mycobacterium smegmatis/drug effects
  • Piperidines/chemical synthesis
  • Polymorphism, Single Nucleotide/drug effects
  • Pseudomonas putida/drug effects
  • Structure-Activity Relationship
  • Tumor Cells, Cultured

Cite this