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 journalArticlepeer-review

9 Citations (Scopus)
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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 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

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