A Dual-Mechanism Antibiotic Kills Gram-Negative Bacteria and Avoids Drug Resistance
2020
Martin, James K. | Sheehan, Joseph P. | Bratton, Benjamin P. | Moore, Gabriel M. | Mateus, Andre | Li, Sophia Hsin-Jung | Kim, Hahn | Rabinowitz, Joshua D. | Typas, Athanasios | Savitski, Mikhail M. | Wilson, Maxwell Z. | Gitai, Zemer
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.
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