A Dual-Mechanism Antibiotic Kills Gram-Negative Bacteria and Avoids Drug Resistance

Cell. 2020 Jun 25;181(7):1518-1532.e14. doi: 10.1016/j.cell.2020.05.005. Epub 2020 Jun 3.


The rise of antibiotic resistance and declining discovery of new antibiotics has created a global health crisis. Of particular concern, no new antibiotic classes have been approved for treating Gram-negative pathogens in decades. Here, we characterize a compound, SCH-79797, that kills both Gram-negative and Gram-positive bacteria through a unique dual-targeting mechanism of action (MoA) with undetectably low resistance frequencies. To characterize its MoA, we combined quantitative imaging, proteomic, genetic, metabolomic, and cell-based assays. This pipeline demonstrates that SCH-79797 has two independent cellular targets, folate metabolism and bacterial membrane integrity, and outperforms combination treatments in killing methicillin-resistant Staphylococcus aureus (MRSA) persisters. Building on the molecular core of SCH-79797, we developed a derivative, Irresistin-16, with increased potency and showed its efficacy against Neisseria gonorrhoeae in a mouse vaginal infection model. This promising antibiotic lead suggests that combining multiple MoAs onto a single chemical scaffold may be an underappreciated approach to targeting challenging bacterial pathogens.

Keywords: Acinetobacter baumannii; Gram-negative pathogens; Neisseria gonorrhoeae; antibiotics; broad spectrum; dual-target drugs; folate metabolism; membrane disrupting.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Anti-Bacterial Agents / pharmacology
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Drug Resistance, Bacterial / drug effects
  • Drug Resistance, Bacterial / genetics
  • Female
  • Folic Acid / metabolism
  • Gram-Negative Bacteria / drug effects*
  • Gram-Positive Bacteria / drug effects
  • HEK293 Cells
  • Humans
  • Male
  • Methicillin-Resistant Staphylococcus aureus / drug effects
  • Mice
  • Mice, Inbred BALB C
  • Microbial Sensitivity Tests
  • Ovariectomy
  • Proteomics
  • Pseudomonas aeruginosa / drug effects
  • Pyrroles / metabolism*
  • Pyrroles / pharmacology*
  • Quinazolines / metabolism*
  • Quinazolines / pharmacology*


  • Anti-Bacterial Agents
  • N3-cyclopropyl-7-((4-(1-methylethyl)phenyl)methyl)-7H-pyrrolo(3, 2-f)quinazoline-1,3-diamine
  • Pyrroles
  • Quinazolines
  • Folic Acid