A multidisciplinary approach combining natural product degradation, fragment synthesis, bioinformatics and NMR spectroscopy was used.

The kalimantacins make up a family of hybrid polyketidenonribosomal peptide-derived natural products that display potent and selective antibiotic activity against multidrug resistant strains of Staphylococcus aureus. Herein, we report the first total synthesis of kalimantacin A, in which three fragments are prepared and then united via Sonogashira and amide couplings. The enantioselective synthetic approach is convergent, unlocking routes to further kalimantacins and analogues for structure−activity relationship studies and clinical evaluation.