TY - JOUR T1 - A dual-mechanism antibiotic targets Gram-negative bacteria and avoids drug resistance JF - bioRxiv DO - 10.1101/2020.03.12.984229 SP - 2020.03.12.984229 AU - James K. Martin AU - Maxwell Z. Wilson AU - Gabriel M. Moore AU - Joseph P. Sheehan AU - André Mateus AU - Sophia Hsin-Jung Li AU - Benjamin P. Bratton AU - Hahn Kim AU - Joshua D. Rabinowitz AU - Athanasios Typas AU - Mikhail M. Savitski AU - Zemer Gitai Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/03/13/2020.03.12.984229.abstract N2 - 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. In an animal host model, SCH-79797 reduces pathogenesis of Acinetobacter baumannii, a drug-resistant Gram-negative pathogen. To characterize the MoA of SCH-79797 we combined quantitative imaging, proteomic, genetic, metabolomic, and cell-based assays. This pipeline shows that SCH-79797 has two independent cellular targets, folate metabolism and bacterial membrane integrity, and outperforms combination treatments with other antifolates and membrane disruptors in killing MRSA persisters. Thus, SCH-79797 represents a promising lead antibiotic and suggests that combining multiple MoAs onto a single chemical scaffold may be an underappreciated approach to target challenging bacterial pathogens. ER -