title: Harmaline and its Derivatives Against the Infectious Multi-Drug Resistant Escherichia coli.
abstract: BACKGROUND
  Multidrug resistance (MDR) is a major challenge in the treatment of infectious diseases. The MDR in urinary tract infection causing bacteria, such as Escherichia coli, has made treatment of UTI very difficult.
  
  
  OBJECTIVE
  The aims of the current study were to synthesize a library of harmaline derivatives, and to evaluate their activity against various strains of multi-drug resistance (MDR) E. coli.
  
  
  METHODS
  Harmaline derivatives were synthesized by the reaction of harmaline (1) with various acid halides and anhydrides. These compounds were subjected to susceptibility determination by in vitro MTT assay. The changes in morphology of the bacterial cells after the treatment with harmaline (1) and its new derivatives 2 and 3 were studied through scanning electron, atomic force and fluorescence microscopy. Effect of harmaline and its derivatives on the production of Reactive Oxygen Species (ROS) in MDR E. coli was assessed through lucigenin chemiluminescence assays.
  
  
  RESULTS
  The selected compounds assisted the fluorescently labeled dye DiBAC4(3) to bind to the lipid rich intra-cellular entities, and thus produced a sharp green fluorescence by easily penetrating into the compound-induced depolarized membrane of MDR E. coli. These compounds have also triggered a significant generation of ROS from bacterial cells as compared to the conventional antibiotics. The current study demonstrated that harmaline (1), and its derivatives 2 and 3 were identified as anti-MDR agents against MDR strains of E. coli. Antibacterial effect of compounds 1-3 on MDR E. coli is possibly due to membrane depolarization due to ROS-induced damage to the bacterial cell membrane.
  
  
  CONCLUSIONS
  Harmaline and its derivatives were identified as anti-MDR agents against various highly resistant and Pakistani MDR clinical isolates of E. coli. These compounds may serve as the leads for further studies towards the development of treatment against the infections caused by MDR E. coli.
authors.affiliation: H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi-75270, Pakistan.
authors.forename: Hina
authors.initials: H
authors.lastname: Siddiqui
authors.affiliation: H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi-75270, Pakistan.
authors.forename: Sehar
authors.initials: S
authors.lastname: Tasneem
authors.affiliation: H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi-75270, Pakistan.
authors.forename: Saba
authors.initials: S
authors.lastname: Farooq
authors.affiliation: H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi-75270, Pakistan.
authors.forename: Amtul
authors.initials: A
authors.lastname: Sami
authors.affiliation: H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi-75270, Pakistan.
authors.forename: Atta-Ur
authors.initials: AU
authors.lastname: Rahman
authors.affiliation: H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi-75270, Pakistan.
authors.forename: Muhammad I
authors.initials: MI
authors.lastname: Choudhary
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001549:Benzamides / Q000138:chemical synthesis / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects; D004926:Escherichia coli / Q000187:drug effects*; D006246:Harmaline / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D007211:Indoles / Q000138:chemical synthesis / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D008856:Microscopy, Fluorescence; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D001549:Benzamides; D007211:Indoles; C000622917:N-(2-(2-acetyl-6-methoxy-1H-indol-3-yl)ethyl)-2-chloro-4-nitrobenzamide; C000622916:N-(2-(2-acetyl-6-methoxy-1H-indol-3-yl)ethyl)-3-chlorobenzamide; D017382:Reactive Oxygen Species; D006246:Harmaline
keywords: Bacterial cell; Escherichia coli; harmaline; membrane potential; multi-drug resistance; reactive oxygen species