Journal Article

A new antibiotic selectively kills Gramnegative pathogens

Manuse, Sylvie, Hiller, Sebastian, Imai, Yu, Mori, Miho, Nelson, Karen E, Honrao, Chandrashekhar, Meyer, Kirsten J, Makriyannis, Alexandros, O'Rourke, Aubrie, Schäberle, Till F, Iinishi, Akira, Caboni, Mariaelena, Wuisan, Zerlina G, Typas, Athanasios, Kaur, Hundeep, Noinaj, Nicholas, Böhringer, Nils, Mateus, André, Ma, Xiaoyu, Favre-Godal, Quentin, Ghiglieri, Meghan, Espinoza, Josh L, Lewis, Kim, D'Onofrio, Anthony, Niles, Samantha, Guo, Jason J, Green, Robert, Linares-Otoya, Luis, Wu, Runrun, Savitski, Mikhail M

2019

نظرة عامة

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.

• الناشر: Nature Publishing Group
• موضوع: Amino acids / Animal models / Antibiotics / Antimicrobial agents / Bacteria / Carbon / Drug development / Drug resistance / E coli / Entomopathogenic nematodes / Enzymes / Genomes / Gram-negative bacteria / Membrane proteins / Microbiomes / Microorganisms / Natural products / Nematodes / NMR / Nuclear magnetic resonance / Outer membrane proteins / Pathogens / Peptides / Permeability / Photorhabdus / Post-translation / Scientific imaging / Symbionts