@article{170771,
  author = {James Martin and Joseph Sheehan and Benjamin Bratton and Gabriel Moore and Andr{\'e} Mateus and Sophia Hsin-Jung Li and Hahn Kim and Joshua Rabinowitz and Athanasios Typas and Mikhail Savitski and Maxwell Wilson and Zemer Gitai},
  title = {A Dual-Mechanism Antibiotic Kills Gram-Negative Bacteria and Avoids Drug Resistance},
  abstract = {<p>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.</p>
},
  year = {2020},
  journal = {Cell},
  volume = {181},
  pages = {1518-1532.e14},
  month = {06/2020},
  issn = {1097-4172},
  doi = {10.1016/j.cell.2020.05.005},
  language = {eng},
}