Promiscuous indolyl vinyl isonitrile synthases in the biogenesis and diversification of hapalindole-type alkaloids.

The hapalindole-type alkaloids naturally show striking late stage diversification of what was believed to be a conserved intermediate, -indolyl vinyl isonitrile (). Here we demonstrate enzymatically, as well as through applying a synthetic biology approach, that the pathway generating (itself, a potent natural broad-spectrum antibiotic) is also dramatically flexible. We harness this to enable early stage diversification of the natural product and generation of a wide range of halo-analogues of . This approach allows the preparatively useful generation of a series of antibiotics with increased lipophilicity over that of the parent antibiotic.