Optimized arylomycins are a new class of Gram-negative antibiotics

Nature. 2018 Sep;561(7722):189-194. doi: 10.1038/s41586-018-0483-6. Epub 2018 Sep 12.


Multidrug-resistant bacteria are spreading at alarming rates, and despite extensive efforts no new class of antibiotic with activity against Gram-negative bacteria has been approved in over fifty years. Natural products and their derivatives have a key role in combating Gram-negative pathogens. Here we report chemical optimization of the arylomycins-a class of natural products with weak activity and limited spectrum-to obtain G0775, a molecule with potent, broad-spectrum activity against Gram-negative bacteria. G0775 inhibits the essential bacterial type I signal peptidase, a new antibiotic target, through an unprecedented molecular mechanism. It circumvents existing antibiotic resistance mechanisms and retains activity against contemporary multidrug-resistant Gram-negative clinical isolates in vitro and in several in vivo infection models. These findings demonstrate that optimized arylomycin analogues such as G0775 could translate into new therapies to address the growing threat of multidrug-resistant Gram-negative infections.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / classification*
  • Anti-Bacterial Agents / pharmacology*
  • Biocatalysis / drug effects
  • Biological Products / classification
  • Biological Products / pharmacology
  • Drug Resistance, Multiple, Bacterial / drug effects
  • Escherichia coli / enzymology
  • Gram-Negative Bacteria / drug effects*
  • Gram-Negative Bacteria / enzymology
  • Gram-Negative Bacteria / pathogenicity
  • Gram-Negative Bacterial Infections / drug therapy
  • Gram-Negative Bacterial Infections / microbiology
  • Klebsiella pneumoniae / drug effects
  • Klebsiella pneumoniae / enzymology
  • Klebsiella pneumoniae / pathogenicity
  • Lysine / metabolism
  • Membrane Proteins / antagonists & inhibitors
  • Microbial Sensitivity Tests
  • Peptides, Cyclic / chemistry
  • Peptides, Cyclic / pharmacology*
  • Porins
  • Protein Binding
  • Protein Domains
  • Serine Endopeptidases
  • Substrate Specificity


  • Anti-Bacterial Agents
  • Biological Products
  • Membrane Proteins
  • Peptides, Cyclic
  • Porins
  • arylomycin A-C16
  • Serine Endopeptidases
  • type I signal peptidase
  • Lysine