Hamacanthins are a class of antibacterial bisindole alkaloids isolated from marine sponges. Based on structure-activity relationships and in silico MRSA PK binding analysis of these bisindole alkaloids, the authors designed new hamacanthin B derivatives and evaluated their antibacterial activities against drug-resistant pathogens. Racemates of the synthetic products were resolved into their enantiomers by chiral separation using a cellulose column, and antibacterial activities were compared. Unsaturation of the central heterocyclic ring structure and bromine substitution at the indole moiety were found to enhance the antibacterial activities of hamacanthin B analogues.