A Dual-Mechanism Antibiotic Kills Gram-Negative Bacteria and Avoids Drug Resistance.
A Dual-Mechanism Antibiotic Kills Gram-Negative Bacteria and Avoids Drug Resistance.
复制标题
DOI：
10.1016/j.cell.2020.05.005
复制
发表时间：
2020-06-25
期刊：
影响因子：
64.5
通讯作者：
Gitai Z
中科院分区：
文献类型：
--
作者：
Martin JK 2nd;Sheehan JP;Bratton BP;Moore GM;Mateus A;Li SH;Kim H;Rabinowitz JD;Typas A;Savitski MM;Wilson MZ;Gitai Z
抗生素耐药性的增加和新抗生素发现的减少已经造成了全球健康危机。特别值得关注的是，几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，它通过独特的双靶向作用机制（MoA）杀死革兰氏阴性菌和革兰氏阳性菌，耐药频率低得无法检测。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测定。该管线表明，SCH-79797具有两个独立的细胞靶点，即叶酸代谢和细菌膜完整性，并且在杀灭耐甲氧西林金黄色葡萄球菌（MRSA）持久性方面优于联合治疗。基于SCH-79797的分子核心，我们开发了一种具有更高效价的衍生物Irdyn-16，并在小鼠阴道感染模型中显示了其对淋病奈瑟菌的有效性。这种有前途的抗生素先导物表明，将多种MoA结合到单一化学支架上可能是一种未被充分认识的靶向具有挑战性的细菌病原体的方法。通过两种独立机制杀死革兰氏阳性和革兰氏阴性细菌的化合物可能为未来抗生素的开发提供平台。
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. A compound that kills both Gram-positive and Gram-negative bacteria through two independent mechanisms may provide a platform for the development of future antibiotics.
登录
查看更多内容
影响因子：
3.2
作者：
GUTNICK, D;CALVO, JM;AMES, BN
通讯作者：
AMES, BN
影响因子：
8.4
作者：
Cammarata, Michael;Thyer, Ross;Brodbelt, Jennifer S.
通讯作者：
Brodbelt, Jennifer S.
影响因子：
5.8
作者：
Ahn, HS;Foster, C;Graziano, M
通讯作者：
Graziano, M
影响因子：
4.9
作者：
Karlowsky, JA;Draghi, DC;Sahm, DF
通讯作者：
Sahm, DF
影响因子：
6.4
作者：
Gebhardt MJ;Gallagher LA;Jacobson RK;Usacheva EA;Peterson LR;Zurawski DV;Shuman HA
通讯作者：
Shuman HA