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. Bioassayguided 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.

Lithistid sponges are known to produce a diverse array of compounds ranging from polyketides, cyclic and linear peptides, alkaloids, pigments, lipids, and sterols. A majority of these structurally complex compounds have very potent and interesting biological activities. It has been a decade since a thorough review has been published that summarizes the literature on the natural products reported from this amazing sponge order. This review provides an update on the current taxonomic classification of the Lithistida, describes structures and biological activities of 131 new natural products, and discusses highlights from the total syntheses of 16 compounds from marine sponges of the Order Lithistida providing a compilation of the literature since the last review published in 2002.

Five new marine-derived macrolide compounds, lasonolides C (3), D (4), E (5), F (6), and G (7), have been isolated from the sponge Forcepia sp. along with the parent compound in the series, lasonolide A (1). Their structures were elucidated on the basis of spectral data. Compounds 3-5 inhibit the in vitro proliferation of A-549 human lung adenocarcinoma cells with IC50's of 0.13, 4.5, and 0.31 microM, respectively. Compounds 3-6 inhibit the in vitro proliferation of PANC-1 human pancreatic carcinoma cells with IC50's of 0.38, 4.89, 0.57, and 15.6 microM, respectively. Compound 3 inhibits the in vitro proliferation of the NCI-ADR-RES cell line with an IC50 of 1.12 microM.