Selective Killing Of Dormant Mycobacterium tuberculosis By Marine Natural Products [PublishAheadOfPrint]

The dormant phenotype acquired by Mycobacterium tuberculosis (Mtb) during infection poses a major challenge in disease treatment since these bacilli are tolerant 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 Mtb under both replicating and non-replicating conditions we have identified compounds that are selectively active against dormant Mtb. 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 Mtb we used a luciferase reporter assay and CFU enumeration. The structures of five purified active compounds were defined by NMR and mass spectrometry. We identified two lipid compounds with potent activity towards dormant and actively growing Mtb. One of these was commercially obtained and showed similar activity against Mtb in both screening models. Furthermore, puupehenone-like molecules were purified with potent and selective activity against dormant Mtb. In conclusion, we have identified and characterized antimycobacterial compounds from marine organisms with novel activity profiles which appear to target Mtb pathways conditionally essential for dormancy survival.

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