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

Author(s): Martin, James K; Sheehan, Joseph P; Bratton, Benjamin P; Moore, Gabriel M; Mateus, André; et al

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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.
Publication Date: 25-Jun-2020
Citation: 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.. Cell, 181 (7), 1518 - 1532.e14. doi:10.1016/j.cell.2020.05.005
DOI: doi:10.1016/j.cell.2020.05.005
ISSN: 0092-8674
EISSN: 1097-4172
Pages: 1518 - 1532.e14
Language: eng
Type of Material: Journal Article
Journal/Proceeding Title: Cell
Version: Author's manuscript

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