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.

抗生素耐药性的上升和新抗生素的发现数量下降，造成了全球性健康危机。特别值得关注的是，数十年来，没有新的抗生素类别被批准用于治疗革兰氏阴性病原体。在这里，我们描述了一种化合物SCH-79797，它通过独特的双重靶向作用机制（MoA）杀死了革兰氏阴性菌和革兰氏阳性菌，耐药频率极低。为了表征其MoA，我们结合了定量成像，蛋白质组学，遗传学，代谢组学和基于细胞的检测方法。该研究表明SCH-79797具有两个独立的细胞靶点，叶酸代谢和细菌膜完整性，并且在杀死耐甲氧西林的金黄色葡萄球菌方面优于联合治疗（MRSA）持久性。我们以SCH-79797的分子核心为基础，开发了具有增强效力的衍生物Irresistin-16，并在小鼠阴道感染模型中显示了其对淋病奈瑟氏球菌的功效。这种有前途的抗生素线索表明，将多个MoAs组合到单个化学支架上可能是针对挑战性细菌病原体的一种未被充分认识的方法。