Anti-microbial diterpene alkaloids from the marine sponge Agelas nakamurai

A chemical investigation of the CH₂Cl₂ extract of a sponge Agelas nakamurai guided by the molecular networking approach resulted in the isolation of 7 undescribed N-methylpurine diterpene alkaloids, namely nakamuranine A-G (1-7), in addition to (+)-8-epiagelasine T, agelasine D and (+)-agelamide D. Their structures were characterized by an extensive analysis of the spectroscopic data, including the ECD calculations for the assignment of the absolute configurations. These analogs were detected for antibacterial activity, while nakamuranines E-G and agelasine D showed potent inhibition against S. aureus (ATCC 29213) and MRSA (T144) with MIC = 1-2 μg/mL. Mechanistic studies demonstrated that the bioactive analogs act at membrane to target on the bacterial-specific phospholipid PG and disrupt membrane integrity, thereby exerting a rapid and potent antibacterial effect.