Nature | 1 | Nature https://doi.org/10.1038/s41586-019-1791-1 (2019)
The current need for novel antibiotics is especially acute for drug-resistant Gramnegative pathogens1,2. These microorganisms have a highly restrictive permeability barrier, which limits the penetration of most compounds3,4. As a result, the last class of antibiotics acting against Gram-negative bacteria was developed in the 1960s2. We reason that useful compounds can be found in bacteria that share similar requirements for antibiotics with humans, and focus on Photorhabdus symbionts of entomopathogenic nematode microbiomes. Here we report a new antibiotic that we name darobactin, from a screen of Photorhabdus isolates. Darobactin is coded by a silent operon with little production under laboratory conditions, and is ribosomally synthesized. Darobactin has an unusual structure with two fused rings that form posttranslationally. The compound is active against important Gram-negative pathogens both in vitro and in animal models of infection. Mutants resistant to darobactin map to BamA, an essential chaperone and translocator that folds outer membrane proteins. Our study suggests that bacterial symbionts of animals contain antibiotics that are particularly suitable for development into therapeutics.
Yu Imai1,12, Kirsten J. Meyer1,12, Akira Iinishi1, Quentin Favre-Godal1, Robert Green1, Sylvie Manuse1, Mariaelena Caboni1, Miho Mori1, Samantha Niles1, Meghan Ghiglieri1, Chandrashekhar Honrao2, Xiaoyu Ma2, Jason Guo2,3, Alexandros Makriyannis2,3, Luis Linares-Otoya4, Nils Böhringer4, Zerlina G. Wuisan4, Hundeep Kaur5, Runrun Wu6, Andre Mateus7, Athanasios Typas7, Mikhail M. Savitski7, Josh L. Espinoza8, Aubrie O’Rourke8, Karen E. Nelson8,9, Sebastian Hiller5, Nicholas Noinaj6, Till F. Schäberle4,10,11, Anthony D’Onofrio1 & Kim Lewis1*