Tryptoline-based benzothiazoles re-sensitize MRSA to β-lactam antibiotics

Bioorg Med Chem. 2019 Nov 1;27(21):115095. doi: 10.1016/j.bmc.2019.115095. Epub 2019 Sep 9.

Abstract

Resistance-modifying agents (RMAs) offer a promising solution to combat bacterial antibiotic resistance. Here we report the discovery and structure-activity relationships of a new class of RMAs with a novel tryptoline-based benzothiazole scaffold. Our most potent compound in this series (4ad) re-sensitizes multiple MRSA strains to cephalosporins at low concentrations (2 μg/mL) and has low mammalian cytotoxicity with a half growth inhibitory concentration (GI50) > 100 μg/mL in human cervical carcinoma (HeLa) cells. In addition, the same core scaffold with different substitutions also gives good antibacterial activity against MRSA.

Keywords: Bacterial antibiotic resistance; Methicillin-resistant Staphylococcus aureus (MRSA); Resistance-modifying agents (RMAs); Structure-activity relationship (SAR); Tryptoline-based benzothiazoles; β-lactam antibiotics.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Anti-Bacterial Agents / chemical synthesis
  • Anti-Bacterial Agents / pharmacology*
  • Anti-Bacterial Agents / toxicity
  • Benzothiazoles / chemical synthesis
  • Benzothiazoles / pharmacology*
  • Benzothiazoles / toxicity
  • Carbolines / chemical synthesis
  • Carbolines / pharmacology*
  • Carbolines / toxicity
  • Cefazolin / pharmacology
  • Cefuroxime / pharmacology
  • Drug Resistance, Bacterial / drug effects*
  • HeLa Cells
  • Humans
  • Methicillin-Resistant Staphylococcus aureus / drug effects*
  • Microbial Sensitivity Tests
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Anti-Bacterial Agents
  • Benzothiazoles
  • Carbolines
  • tryptoline
  • Cefazolin
  • Cefuroxime