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Selective Killing of Dormant Mycobacterium tuberculosis by Marine Natural Products.
Rodrigues Felix, Carolina; Gupta, Rashmi; Geden, Sandra; Roberts, Jill; Winder, Priscilla; Pomponi, Shirley A; Diaz, Maria Cristina; Reed, John K; Wright, Amy E; Rohde, Kyle H.
Affiliation
  • Rodrigues Felix C; Division of Immunity and Pathogenesis, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida, USA.
  • Gupta R; Division of Immunity and Pathogenesis, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida, USA.
  • Geden S; Division of Immunity and Pathogenesis, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida, USA.
  • Roberts J; Harbor Branch Oceanographic Institute, Florida Atlantic University, Fort Pierce, Florida, USA.
  • Winder P; Harbor Branch Oceanographic Institute, Florida Atlantic University, Fort Pierce, Florida, USA.
  • Pomponi SA; Harbor Branch Oceanographic Institute, Florida Atlantic University, Fort Pierce, Florida, USA.
  • Diaz MC; Harbor Branch Oceanographic Institute, Florida Atlantic University, Fort Pierce, Florida, USA.
  • Reed JK; Harbor Branch Oceanographic Institute, Florida Atlantic University, Fort Pierce, Florida, USA.
  • Wright AE; Harbor Branch Oceanographic Institute, Florida Atlantic University, Fort Pierce, Florida, USA.
  • Rohde KH; Division of Immunity and Pathogenesis, Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, Florida, USA kyle.rohde@ucf.edu.
Article in En | MEDLINE | ID: mdl-28607021
ABSTRACT
The dormant phenotype acquired by Mycobacterium tuberculosis during infection poses a major challenge in disease treatment, since these bacilli show tolerance to front-line drugs. Therefore, it is imperative to find novel compounds that effectively kill dormant bacteria. By screening 4,400 marine natural product samples against dual-fluorescent M. tuberculosis under both replicating and nonreplicating conditions, we have identified compounds that are selectively active against dormant M. tuberculosis This validates our strategy of screening all compounds in both assays as opposed to using the dormancy model as a secondary screen. Bioassay-guided deconvolution enabled the identification of unique pharmacophores active in each screening model. To confirm the activity of samples against dormant M. tuberculosis, we used a luciferase reporter assay and enumerated CFU. The structures of five purified active compounds were defined by nuclear magnetic resonance (NMR) and mass spectrometry. We identified two lipid compounds with potent activity toward dormant and actively growing M. tuberculosis strains. One of these was commercially obtained and showed similar activity against M. tuberculosis in both screening models. Furthermore, puupehenone-like molecules were purified with potent and selective activity against dormant M. tuberculosis In conclusion, we have identified and characterized antimycobacterial compounds from marine organisms with novel activity profiles which appear to target M. tuberculosis pathways that are conditionally essential for dormancy survival.
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Full text: 1 Database: MEDLINE Main subject: Sesquiterpenes / Tuberculosis, Pulmonary / Biological Products / Xanthones / Mycobacterium tuberculosis / Antitubercular Agents Limits: Humans Language: En Year: 2017 Type: Article

Full text: 1 Database: MEDLINE Main subject: Sesquiterpenes / Tuberculosis, Pulmonary / Biological Products / Xanthones / Mycobacterium tuberculosis / Antitubercular Agents Limits: Humans Language: En Year: 2017 Type: Article