title: Identification of the anti-mycobacterial functional properties of piperidinol derivatives.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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.
  
  
  CONCLUSIONS
  Our results indicate that the piperidinol moiety represents an attractive compound class in the pursuit of novel anti-tubercular agents.
  
  
  BACKGROUND
  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.
authors.affiliation: School of Life Sciences, University of Warwick, Coventry, UK.|Department of Chemistry, University of Warwick, Coventry, UK.
authors.forename: Collette S
authors.initials: CS
authors.lastname: Guy
authors.affiliation: School of Life Sciences, University of Warwick, Coventry, UK.
authors.forename: Esther
authors.initials: E
authors.lastname: Tichauer
authors.affiliation: Medical School, University of Warwick, Coventry, UK.
authors.forename: Gemma L
authors.initials: GL
authors.lastname: Kay
authors.affiliation: Department of Chemistry, University of Warwick, Coventry, UK.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Phillips
authors.affiliation: Department of Chemistry, University of Warwick, Coventry, UK.
authors.forename: Trisha L
authors.initials: TL
authors.lastname: Bailey
authors.affiliation: School of Life Sciences, University of Warwick, Coventry, UK.
authors.forename: James
authors.initials: J
authors.lastname: Harrison
authors.affiliation: School of Life Sciences, University of Warwick, Coventry, UK.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Furze
authors.affiliation: Medical School, University of Warwick, Coventry, UK.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Millard
authors.affiliation: Department of Chemistry, University of Warwick, Coventry, UK.|Medical School, University of Warwick, Coventry, UK.
authors.forename: Matthew I
authors.identifier: http://orcid.org/0000-0002-8297-1278
authors.initials: MI
authors.lastname: Gibson
authors.affiliation: Medical School, University of Warwick, Coventry, UK.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Pallen
authors.affiliation: School of Life Sciences, University of Warwick, Coventry, UK.
authors.forename: Elizabeth
authors.identifier: http://orcid.org/0000-0001-6245-1614
authors.initials: E
authors.lastname: Fullam
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004926:Escherichia coli / Q000187:drug effects*; D006801:Humans; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D020102:Mycobacterium smegmatis / Q000187:drug effects* / Q000235:genetics; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D020641:Polymorphism, Single Nucleotide / Q000187:drug effects / Q000235:genetics; D016958:Pseudomonas putida / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000900:Anti-Bacterial Agents; D010880:Piperidines