A new antibiotic selectively kills Gram-negative pathogens

Yu Imai, Kirsten J. Meyer, Akira Iinishi, Quentin Favre-Godal, Robert Green, Sylvie Manuse, Mariaelena Caboni, Miho Mori, Samantha Niles, Meghan Ghiglieri, Chandrashekhar Honrao, Xiaoyu Ma, Jason J. Guo, Alexandros Makriyannis, Luis Linares-Otoya, Nils Böhringer, Zerlina G. Wuisan, Hundeep Kaur, Runrun Wu, André Mateus, Athanasios Typas, Mikhail M. Savitski, Josh L. Espinoza, Aubrie O’Rourke, Karen E. Nelson, Sebastian Hiller, Nicholas Noinaj, Till F. Schäberle, Anthony D’Onofrio and Kim Lewis ()
Additional contact information
Yu Imai: Northeastern University
Kirsten J. Meyer: Northeastern University
Akira Iinishi: Northeastern University
Quentin Favre-Godal: Northeastern University
Robert Green: Northeastern University
Sylvie Manuse: Northeastern University
Mariaelena Caboni: Northeastern University
Miho Mori: Northeastern University
Samantha Niles: Northeastern University
Meghan Ghiglieri: Northeastern University
Chandrashekhar Honrao: Northeastern University
Xiaoyu Ma: Northeastern University
Jason J. Guo: Northeastern University
Alexandros Makriyannis: Northeastern University
Luis Linares-Otoya: Justus-Liebig-University of Giessen
Nils Böhringer: Justus-Liebig-University of Giessen
Zerlina G. Wuisan: Justus-Liebig-University of Giessen
Hundeep Kaur: University of Basel
Runrun Wu: Purdue University
André Mateus: European Molecular Biology Laboratory
Athanasios Typas: European Molecular Biology Laboratory
Mikhail M. Savitski: European Molecular Biology Laboratory
Josh L. Espinoza: J. Craig Venter Institute
Aubrie O’Rourke: J. Craig Venter Institute
Karen E. Nelson: J. Craig Venter Institute
Sebastian Hiller: University of Basel
Nicholas Noinaj: Purdue University
Till F. Schäberle: Justus-Liebig-University of Giessen
Anthony D’Onofrio: Northeastern University
Kim Lewis: Northeastern University

Nature, 2019, vol. 576, issue 7787, 459-464

Abstract: Abstract The current need for novel antibiotics is especially acute for drug-resistant Gram-negative 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 that acted 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, which was obtained using 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 post-translationally. The compound is active against important Gram-negative pathogens both in vitro and in animal models of infection. Mutants that are 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.

Date: 2019
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DOI: 10.1038/s41586-019-1791-1

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