Synthesis and evaluation of 1,3,4-oxadiazole derivatives for development as broad-spectrum antibiotics

Bioorg Med Chem. 2019 Nov 1;27(21):115097. doi: 10.1016/j.bmc.2019.115097. Epub 2019 Sep 10.

Abstract

The reality and intensity of antibiotic resistance in pathogenic bacteria calls for the rapid development of new antimicrobial drugs. In bacteria, trans-translation is the primary quality control mechanism for rescuing ribosomes arrested during translation. Because trans-translation is absent in eukaryotes but necessary to avoid ribosomal stalling and therefore essential for bacterial survival, it is a promising target either for novel antibiotics or for improving the activities of the protein synthesis inhibitors already in use. Oxadiazole derivatives display strong bactericidal activity against a large number of bacteria, but their effects on trans-translation were recently questioned. In this work, a series of new 1,3,4-oxadiazole derivatives and analogs were synthesized and assessed for their efficiency as antimicrobial agents against a wide range of gram-positive and gram-negative pathogenic strains. Despite the strong antimicrobial activity observed in these molecules, it turns out that they do not target trans-translation in vivo, but they definitely act on other cellular pathways.

Keywords: Antibiotics; Oxadiazoles; Ribosome; Trans-translation; tmRNA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / chemical synthesis
  • Anti-Bacterial Agents / pharmacology*
  • Anti-Bacterial Agents / toxicity
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Drug Design
  • Drug Synergism
  • Gram-Negative Bacteria / drug effects
  • Gram-Positive Bacteria / drug effects
  • Humans
  • Microbial Sensitivity Tests
  • Oxadiazoles / chemical synthesis
  • Oxadiazoles / pharmacology*
  • Oxadiazoles / toxicity

Substances

  • Anti-Bacterial Agents
  • Oxadiazoles