The antibiotic darobactin mimics a β-strand to inhibit outer membrane insertase

Hundeep Kaur, Roman P. Jakob, Jan K. Marzinek, Robert Green, Yu Imai, Jani Reddy Bolla, Elia Agustoni, Carol V. Robinson, Peter J. Bond, Kim Lewis (), Timm Maier () and Sebastian Hiller ()
Additional contact information
Hundeep Kaur: Biozentrum, University of Basel
Roman P. Jakob: Biozentrum, University of Basel
Jan K. Marzinek: Bioinformatics Institute (A*STAR)
Robert Green: Northeastern University
Yu Imai: Northeastern University
Jani Reddy Bolla: University of Oxford
Elia Agustoni: Biozentrum, University of Basel
Carol V. Robinson: University of Oxford
Peter J. Bond: Bioinformatics Institute (A*STAR)
Kim Lewis: Northeastern University
Timm Maier: Biozentrum, University of Basel
Sebastian Hiller: Biozentrum, University of Basel

Nature, 2021, vol. 593, issue 7857, 125-129

Abstract: Abstract Antibiotics that target Gram-negative bacteria in new ways are needed to resolve the antimicrobial resistance crisis1–3. Gram-negative bacteria are protected by an additional outer membrane, rendering proteins on the cell surface attractive drug targets4,5. The natural compound darobactin targets the bacterial insertase BamA6—the central unit of the essential BAM complex, which facilitates the folding and insertion of outer membrane proteins7–13. BamA lacks a typical catalytic centre, and it is not obvious how a small molecule such as darobactin might inhibit its function. Here we resolve the mode of action of darobactin at the atomic level using a combination of cryo-electron microscopy, X-ray crystallography, native mass spectrometry, in vivo experiments and molecular dynamics simulations. Two cyclizations pre-organize the darobactin peptide in a rigid β-strand conformation. This creates a mimic of the recognition signal of native substrates with a superior ability to bind to the lateral gate of BamA. Upon binding, darobactin replaces a lipid molecule from the lateral gate to use the membrane environment as an extended binding pocket. Because the interaction between darobactin and BamA is largely mediated by backbone contacts, it is particularly robust against potential resistance mutations. Our results identify the lateral gate as a functional hotspot in BamA and will allow the rational design of antibiotics that target this bacterial Achilles heel.

Date: 2021
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DOI: 10.1038/s41586-021-03455-w

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