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; Kim Lewis

doi:10.1038/s41586-019-1791-1

A new antibiotic selectively kills Gram-negative pathogens

Nature. 2019 Dec;576(7787):459-464. doi: 10.1038/s41586-019-1791-1. Epub 2019 Nov 20.

Authors

Yu Imai¹, Kirsten J Meyer¹, Akira Iinishi¹, Quentin Favre-Godal¹, Robert Green¹, Sylvie Manuse¹, Mariaelena Caboni¹, Miho Mori¹, Samantha Niles¹, Meghan Ghiglieri¹, Chandrashekhar Honrao², Xiaoyu Ma², Jason J Guo^{2

3}, Alexandros Makriyannis², Luis Linares-Otoya⁴, Nils Böhringer⁴, Zerlina G Wuisan⁴, Hundeep Kaur⁵, Runrun Wu^{6

7}, André Mateus⁸, Athanasios Typas⁸, Mikhail M Savitski⁸, Josh L Espinoza^{9

10}, Aubrie O'Rourke^{9

10}, Karen E Nelson^{9

10

11

12}, Sebastian Hiller⁵, Nicholas Noinaj^{6

7}, Till F Schäberle^{4

13

14}, Anthony D'Onofrio¹, Kim Lewis¹⁵

Affiliations

¹ Antimicrobial Discovery Center, Department of Biology, Northeastern University, Boston, MA, USA.
² Center for Drug Discovery, Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, USA.
³ Barnett Institute for Chemical and Biological Analysis, Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA, USA.
⁴ Institute for Insect Biotechnology, Justus-Liebig-University of Giessen, Giessen, Germany.
⁵ Biozentrum, University of Basel, Basel, Switzerland.
⁶ Purdue Institute of Inflammation, Immunology and Infectious Disease, Purdue University, West Lafayette, IN, USA.
⁷ Markey Center for Structural Biology, Department of Biological Sciences, Purdue University, West Lafayette, IN, USA.
⁸ Genome Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany.
⁹ Department of Human Biology, J. Craig Venter Institute, La Jolla, CA, USA.
¹⁰ Department of Genomic Medicine, J. Craig Venter Institute, La Jolla, CA, USA.
¹¹ Department of Human Biology, J. Craig Venter Institute, Rockville, MD, USA.
¹² Department of Genomic Medicine, J. Craig Venter Institute, Rockville, MD, USA.
¹³ Department of Bioresources, Fraunhofer Institute for Molecular Biology and Applied Ecology, Giessen, Germany.
¹⁴ German Center for Infection Research (DZIF), Partner Site Giessen-Marburg-Langen, Giessen, Germany.
¹⁵ Antimicrobial Discovery Center, Department of Biology, Northeastern University, Boston, MA, USA. k.lewis@neu.edu.

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 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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anti-Bacterial Agents / chemistry
Anti-Bacterial Agents / isolation & purification*
Anti-Bacterial Agents / pharmacology*
Bacterial Outer Membrane Proteins / antagonists & inhibitors
Bacterial Outer Membrane Proteins / chemistry
Bacterial Outer Membrane Proteins / genetics
Bacterial Outer Membrane Proteins / metabolism
Cell Line
Disease Models, Animal
Drug Discovery
Drug Resistance, Microbial / drug effects
Drug Resistance, Microbial / genetics
Escherichia coli Proteins / antagonists & inhibitors
Escherichia coli Proteins / chemistry
Escherichia coli Proteins / genetics
Escherichia coli Proteins / metabolism
Female
Gastrointestinal Microbiome / drug effects
Gram-Negative Bacteria / drug effects*
Gram-Negative Bacteria / genetics
Gram-Negative Bacteria / pathogenicity*
Humans
Mice
Microbial Sensitivity Tests
Microbial Viability / drug effects
Mutation
Nematoda / microbiology
Operon / genetics
Phenylpropionates / isolation & purification*
Phenylpropionates / pharmacology*
Photorhabdus / chemistry
Photorhabdus / genetics
Photorhabdus / isolation & purification
Substrate Specificity
Symbiosis

Substances

Anti-Bacterial Agents
Bacterial Outer Membrane Proteins
BamA protein, E coli
Escherichia coli Proteins
Phenylpropionates
darobactin

Abstract

Publication types

MeSH terms

Substances

Grants and funding