Selective Killing Of Dormant Mycobacterium Tuberculosis By Marine Natural Products

Keywords

Dormancy; Drug discovery; Drug screening; Marine natural products; Mycobacterium tuberculosis; Natural antimicrobial products; Tuberculosis

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.

Publication Date

8-1-2017

Publication Title

Antimicrobial Agents and Chemotherapy

Volume

61

Issue

8

Document Type

Article

Personal Identifier

scopus

DOI Link

https://doi.org/10.1128/AAC.00743-17

Socpus ID

85026424080 (Scopus)

Source API URL

https://api.elsevier.com/content/abstract/scopus_id/85026424080

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