A dual-mechanism antibiotic kills Gram-negative bacteria and avoids drug resistance

Martin, James K; Sheehan, Joseph P; Bratton, Benjamin P; Moore, Gabriel M; Mateus, André; Li, Sophia Hsin-Jung; Kim, Hahn; Rabinowitz, Joshua D; Typas, Athanasios; Savitski, Mikhail M; Wilson, Maxwell Z; Gitai, Zemer
Issue date: 20 May 2020
Cite as:
Martin, James K, Sheehan, Joseph P, Bratton, Benjamin P, Moore, Gabriel M, Mateus, André, Li, Sophia Hsin-Jung, Kim, Hahn, Rabinowitz, Joshua D, Typas, Athanasios, Savitski, Mikhail M, Wilson, Maxwell Z, & Gitai, Zemer. (2020). A dual-mechanism antibiotic kills Gram-negative bacteria and avoids drug resistance [Data set]. https://doi.org/10.34770/rypq-hp25
  author      = {Martin, James K and
                Sheehan, Joseph P and
                Bratton, Benjamin P and
                Moore, Gabriel M and
                Mateus, André and
                Li, Sophia Hsin-Jung and
                Kim, Hahn and
                Rabinowitz, Joshua D and
                Typas, Athanasios and
                Savitski, Mikhail M and
                Wilson, Maxwell Z and
                Gitai, Zemer},
  title       = {{A dual-mechanism antibiotic kills Gram-n
                egative bacteria and avoids drug resista
  year        = 2020,
  url         = {https://doi.org/10.34770/rypq-hp25}

The rise of antibiotic resistance and declining discovery of new antibiotics have 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 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 gonorrheae 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.

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# Filename Description Filesize
1 SCH_fluorescenceAndMetabolism_Data.tar.gz 635 MB
2 README.txt 1.18 KB