Abstract
Tuberculosis is the leading cause of death due to infectious disease worldwide. There is an urgent need for more effective compounds against this pathogen to control the disease. Investigation of the anti-mycobacterial activity of a deep-water sponge of the genus Plakina revealed the presence of a new steroidal alkaloid of the plakinamine class, which we have given the common name plakinamine P. Its structure is most similar to plakinamine L, which also has an acyclic side chain. Careful dissection of the nuclear magnetic resonance data, collected in multiple solvents, suggests that the dimethyl amino group at the 3 position is in an equatorial rather than axial position unlike previously reported plakinamines. Plakinamine P was bactericidal against M. tuberculosis, and exhibited moderate activity against other mycobacterial pathogens, such as M. abscessus and M. avium. Furthermore, it had low toxicity against J774 macrophages, yielding a selectivity index (SI, or IC50/MIC) of 8.4. In conclusion, this work provides a promising scaffold to the tuberculosis drug discovery pipeline. Future work to determine the molecular target of this compound may reveal a pathway essential for M. tuberculosis survival during infection.
Highlights
Mycobacterium tuberculosis (Mtb) is the causative agent of the primarily pulmonary disease tuberculosis (TB)
Sea Link I manned submersible at a depth of 93 m off Crooked Island, the Bahamas, and stored at
The major global health threat posed by Mtb infections is intensified by the difficulty to treat TB
Summary
Mycobacterium tuberculosis (Mtb) is the causative agent of the primarily pulmonary disease tuberculosis (TB). 10 million new cases of TB are diagnosed every year worldwide, and 5% of these are caused by multidrug-resistant strains of Mtb, rendering the disease extremely difficult to control [1]. There is an urgent need for novel compounds that are more effective against this pathogen, capable of shortening treatment time, and killing drug-resistant strains of Mtb. Recently, a large-scale screen of a marine natural products (MNP) library containing 4400 prefractionated peak fraction samples yielded highly potent inhibitors of Mtb [3]. A novel plakinamine was discovered with potent bactericidal activity against Mtb. We have elucidated the structure of this novel compound and further characterized
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