Quinazoline-Based Antivirulence Compounds Selectively Target Salmonella PhoP/PhoQ Signal Transduction System
Quinazoline-Based Antivirulence Compounds Selectively Target Salmonella PhoP/PhoQ Signal Transduction System
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DOI：
10.1128/aac.01744-19
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发表时间：
2020-01-01
影响因子：
4.9
通讯作者：
Garcia Vescovi, Eleonora
中科院分区：
文献类型：
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作者：
Ayelen Carabajal, Maria;Asquith, Christopher R. M.;Garcia Vescovi, Eleonora
细菌病原菌之间迅速出现的多药耐药已成为本世纪人类健康的重大挑战。因此，开发下一代抗菌化合物是当务之急。双组分信号转导系统(TCS)是一种刺激-反应耦合装置，使细菌能够感知并阐述对不断变化的环境条件，包括病原菌在宿主内部面临的挑战的适应性反应。TCS存在于细菌中，但在动物界中不存在，这使它们成为寻找新的抗菌化合物的有吸引力的目标。在肠沙门氏菌中，Phop/PhoQ双组分系统控制关键表型的表达，这些表型定义了病原体在宿主中建立感染的能力。我们现在报告从葛兰素史克公布的一组激酶抑制因子中筛选出686种化合物，该试验是在高通量全细胞试验中针对鼠伤寒沙门氏菌Phop/PhoQ进行的。我们鉴定了一系列喹唑啉化合物，这些化合物显示了Phop/PhoQ激活基因的选择性和有效下调，并定义了它们疗效所需的结构属性。我们证明它们的生物活性是由于通过与其催化域的相互作用而抑制了PhoQ传感器的自激酶活性，作为ATP结合的竞争性抑制剂。虽然没有细胞毒性，但HIT分子通过阻断鼠伤寒沙门氏菌在巨噬细胞内的复制而显示出抗病毒作用。总之，这些特点使这些喹唑啉化合物脱颖而出，成为开发抗击沙门氏菌病的治疗干预措施的令人兴奋的线索。
The rapid emergence of multidrug resistance among bacterial pathogens has become a significant challenge to human health in our century. Therefore, development of next-generation antibacterial compounds is an urgent need. Two-component signal transduction systems (TCS) are stimulus-response coupling devices that allow bacteria to sense and elaborate adaptive responses to changing environmental conditions, including the challenges that pathogenic bacteria face inside the host. The differential presence of TCS, present in bacteria but absent in the animal kingdom, makes them attractive targets in the search for new antibacterial compounds. In Salmonella enterica, the PhoP/PhoQ two-component system controls the expression of crucial phenotypes that define the ability of the pathogen to establish infection in the host. We now report the screening of 686 compounds from a GlaxoSmithKline published kinase inhibitor set in a high-throughput whole-cell assay that targets Salmonella enterica serovar Typhimurium PhoP/PhoQ. We identified a series of quinazoline compounds that showed selective and potent downregulation of PhoP/PhoQ-activated genes and define structural attributes required for their efficacy. We demonstrate that their bioactivity is due to repression of the PhoQ sensor autokinase activity mediated by interaction with its catalytic domain, acting as competitive inhibitors of ATP binding. While noncytotoxic, the hit molecules exhibit antivirulence effect by blockage of S. Typhimurium intramacrophage replication. Together, these features make these quinazoline compounds stand out as exciting leads to develop a therapeutic intervention to fight salmonellosis.