Screening of diverse marine invertebrate extracts identified Lissoclinotoxin F, Discodermin B, and other anti-Mycobacterium tuberculosis active compounds

Screening of a marine derived crude natural product extract library, followed by bioactivity guided fractionation, has led to isolation and structural elucidation of 10 natural products as hits active against Mycobacterium tuberculosis (Mtb). Among them, three (3, 4 and 5) were identified for the first time and the remaining 7 compounds (1, 2, 6, 7, 8, 9 and 10) were previously reported, but now assigned with anti-mycobacterial activity. Among identified hits, the oligo cyclic depsipeptide discodermin B (7) exhibited the highest potency with an MIC90 value of 0.5 mu M. The polysufide alkaloid lissoclinotoxin F (1) displayed a good balance of anti Mtb potency (MIC90 = 2.6 mu M) and selectivity (SI = 19 in HEK293 cells). Lissoclinotoxin F (1) was found to be active against intracellular Mtb as well as non-replicating forms of Mtb, with higher activity against Mtb compared to other gram-negative and gram-positive bacteria. Consequently, lissoclinotoxin F (1) could be used as a lead compound for development of new TB drugs. Details regarding screening techniques, structural elucidation and preliminary structural activity relationships (SAR) of the isolated hits are discussed.

Automated summary

Screening and isolation of marine derived crude natural products led to the discovery of 10 hits with activity against Mycobacterium tuberculosis (Mtb). Among them, lissoclinotoxin F (1) showed the highest potency and selectivity, and could be a potential lead compound for the development of new TB drugs.