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

James K. Martin, Joseph P. Sheehan, Benjamin P. Bratton, Gabriel M. Moore, André Mateus, Sophia Hsin Jung Li, Hahn Kim, Joshua D. Rabinowitz, Athanasios Typas, Mikhail M. Savitski, Maxwell Z. Wilson, Zemer Gitai

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1518-1532.e14
JournalCell
Volume181
Issue number7
DOIs
StatePublished - Jun 25 2020

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Keywords

  • Acinetobacter baumannii
  • Gram-negative pathogens
  • Neisseria gonorrhoeae
  • antibiotics
  • broad spectrum
  • dual-target drugs
  • folate metabolism
  • membrane disrupting

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