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A new antibiotic selectively kills Gram-negative pathogens

Imai, Yu and Meyer, Kirsten J. and Iinishi, Akira and Favre-Godal, Quentin and Green, Robert and Manuse, Sylvie and Caboni, Mariaelena and Mori, Miho and Niles, Samantha and Ghiglieri, Meghan and Honrao, Chandrashekhar and Ma, Xiaoyu and Guo, Jason J. and Makriyannis, Alexandros and Linares-Otoya, Luis and Böhringer, Nils and Wuisan, Zerlina G. and Kaur, Hundeep and Wu, Runrun and Mateus, André and Typas, Athanasios and Savitski, Mikhail M. and Espinoza, Josh L. and O'Rourke, Aubrie and Nelson, Karen E. and Hiller, Sebastian and Noinaj, Nicholas and Schäberle, Till F. and D'Onofrio, Anthony and Lewis, Kim. (2019) A new antibiotic selectively kills Gram-negative pathogens. Nature, 576 (7787). pp. 459-464.

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Official URL: https://edoc.unibas.ch/74985/

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Abstract

The current need for novel antibiotics is especially acute for drug-resistant Gram-negative pathogens; 1,2; . These microorganisms have a highly restrictive permeability barrier, which limits the penetration of most compounds; 3,4; . As a result, the last class of antibiotics that acted against Gram-negative bacteria was developed in the 1960s; 2; . 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.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Structural Biology & Biophysics > Structural Biology (Hiller)
UniBasel Contributors:Hiller Odermatt, Sebastian
Item Type:Article, refereed
Article Subtype:Research Article
ISSN:1476-4687
Note:Publication type according to Uni Basel Research Database: Journal article
Identification Number:
Last Modified:16 Dec 2020 04:11
Deposited On:10 Feb 2020 16:45

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