Described is the antimicrobial activity of alkaloid psammaplysins, which are marine natural products. A compound library collected from natural sources in Australia was screened for antimicrobial activity against a panel of Gram-positive and Gram-negative bacteria. Two natural products psammaplysins F (1) and H (2), inhibited the growth of different Gram-positive strains by 80% or more. The activity of these compounds, isolated from marine sponge Pseudoceratina is related to the amine at position C20, where substitution to a urea group reduced the antibacterial activity by 3-fold (psammaplysin G ). The MIC values for (1) and (2) were 42-45 µM against penicillin-resistant S. aureus, and between 40-80 µM against two strains of methicillin-resistant S.aureus (MRSA). Morphological evaluation of treated S. aureus using 3D-structured illumination microscopy indicates that psammaplysin F (1) inhibits equal partitioning of DNA into each daughter cell. Indeed, this is the first report of an alkaloid psammaplysin that targets prokaryotic cell division.