Drug-resistant <em>Staphylococcus aureus</em> is a continuing public health concern, both in the hospital and community settings. Antibacterial compounds that possess novel structural scaffolds and are effective against multiple <em>S. aureus</em> strains, including current drug-resistant ones, are needed. Previously, we have described the chrysophaentins, a family of bisdiarylbutene macrocycles from the chrysophyte alga <em>Chrysophaeum taylori</em> that inhibit the growth of <em>S. aureus</em> and methicillin-resistant <em>S. aureus</em> (MRSA). In this study we have analyzed the geographic variability of chrysophaentin production in <em>C. taylori</em> located at different sites on the island of St. John, U.S. Virgin Islands, and identified two new linear chrysophaentin analogs, E2 and E3. In addition, we have expanded the structure activity relationship through synthesis of fragments comprising conserved portions of the chrysophaentins, and determined the antimicrobial activity of natural chrysophaentins and their synthetic analogs against five diverse <em>S. aureus</em> strains. We find that the chrysophaentins show similar activity against all <em>S. aureus</em> strains, regardless of their drug sensitivity profiles. The synthetic chrysophaentin fragments indeed mimic the natural compounds in their spectrum of antibacterial activity, and therefore represent logical starting points for future medicinal chemistry studies of the natural products and their analogs.