Shipworm symbiosis ecology-guided discovery of an antibiotic that kills colistin-resistant Acinetobacter

Teredinibacter turnerae is an intracellular bacterial symbiont that lives in the gills of wood-eating shipworms, where it is proposed to use antibiotics to defend itself and its animal host. Several biosynthetic gene clusters are conserved in T. turnerae and in their host shipworms around the world, implying that they encode the important defensive antibiotics. Here, we describe the turnercyclamycins, lipopeptide antibiotics encoded in the genomes of all sequenced T. turnerae strains. Turnercyclamycins A and B are bactericidal against challenging Gram-negative pathogens, including Escherichia coli, Klebsiella pneumoniae, and Acinetobacter baumannii, at 1, 2, and 8 µg/mL, respectively. Additionally, these compounds kill colistin-resistant Acinetobacter strains, while lacking toxicity to mammalian cells. Phenotypic screening identified the outer membrane as the likely target. By exploring the inhabitants of environments that select for the properties we require, we can harvest the fruits of evolution to discover compounds with potential to target unmet health needs. Investigating the symbionts of animals, and shipworms in particular, is a powerful example of this principle.