Wang Jianfeng, Liu Bowen, Teng Zihao, Zhou Xuan, Wang Xiyan, Zhang Bing, Lu Gejin, Niu Xiaodi, Yang Yongjun, Deng Xuming
Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University Changchun, China.
Front Cell Infect Microbiol. 2017 Jan 19;7:9. doi: 10.3389/fcimb.2017.00009. eCollection 2017.
The critical roles of sortase A (SrtA) and listeriolysin O (LLO) in pathogenicity render these two virulence factors as ideal targets for the development of anti-virulence agents against infection. Additionally, the structures of SrtA and LLO are highly conserved among the members of sortase enzyme family and cholesterol dependent toxin family. Here, phloretin, a natural polyphenolic compound derived from apples and pears that has little anti- activity, was identified to simultaneously inhibit LLO expression and neutralize SrtA catalytic activity. Phloretin neutralized SrtA activity by causing a conformational change in the protein's active pocket, which prevented engagement with its substrate. Treatment with phloretin simultaneously reduced invasion into host cells and blocked the escape of vacuole-entrapped into cytoplasm. Further, -infected mice that received phloretin showed lower mortality, decreased bacterial burden and reduced pathological injury. Our results demonstrate that phloretin is a promising anti-infective therapeutic for infections caused by due to its simultaneous targeting of SrtA and LLO, which may result in fewer side effects than those caused by other antibiotics.
分选酶A（SrtA）和李斯特菌溶血素O（LLO）在致病性中发挥关键作用，使这两种毒力因子成为开发抗感染抗毒力药物的理想靶点。此外，SrtA和LLO的结构在分选酶家族和胆固醇依赖性毒素家族成员中高度保守。在这里，根皮素是一种源自苹果和梨的天然多酚化合物，几乎没有抗菌活性，被发现能同时抑制LLO表达并中和SrtA催化活性。根皮素通过引起蛋白质活性口袋的构象变化来中和SrtA活性，从而阻止其与底物结合。用根皮素处理同时减少了对宿主细胞的侵袭，并阻止了被液泡包裹的细菌逃逸到细胞质中。此外，接受根皮素治疗的感染小鼠死亡率降低、细菌载量减少且病理损伤减轻。我们的结果表明，根皮素因其同时靶向SrtA和LLO，有望成为治疗感染的抗感染药物，与其他抗生素相比，其副作用可能更少。
