Lyu Yuhan, Yang Fan, Sundaresh Bharathi, Rosconi Federico, van Opijnen Tim, Gao Jianmin
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467, United States.
Department of Biology, Boston College, Chestnut Hill, Massachusetts 02467, United States.
JACS Au. 2024 Jun 20;4(7):2484-2491. doi: 10.1021/jacsau.4c00195. eCollection 2024 Jul 22.
The ever-expanding antibiotic resistance urgently calls for novel antibacterial therapeutics, especially those with a new mode of action. We report herein our exploration of protein-protein interaction (PPI) inhibition as a new mechanism to thwart bacterial pathogenesis. Specifically, we describe potent and specific inhibitors of the pneumococcal surface protein PspC, an important virulence factor that facilitates the infection of Specifically, PspC has been documented to recruit human complement factor H (hFH) to suppress host complement activation and/or promote the bacterial attachment to host tissues. The CCP9 domain of hFH was recombinantly expressed to inhibit the PspC-hFH interaction as demonstrated on live pneumococcal cells. The inhibitor allowed for the first pharmacological intervention of the PspC-hFH interaction. This PPI inhibition reduced pneumococci's attachment to epithelial cells and also resensitized the D39 strain of for opsonization. Importantly, we have further devised covalent versions of CCP9, which afforded long-lasting PspC inhibition with low nanomolar potency. Overall, our results showcase the promise of PPI inhibition for combating bacterial infections as well as the power of covalent inhibitors.
日益扩大的抗生素耐药性迫切需要新型抗菌疗法，尤其是那些具有新作用模式的疗法。我们在此报告我们对蛋白质-蛋白质相互作用（PPI）抑制作为一种对抗细菌致病机制的新探索。具体而言，我们描述了肺炎球菌表面蛋白PspC的强效和特异性抑制剂，PspC是一种重要的毒力因子，有助于肺炎球菌感染。具体来说，已有文献记载PspC可募集人补体因子H（hFH）以抑制宿主补体激活和/或促进细菌附着于宿主组织。hFH的CCP9结构域通过重组表达来抑制PspC-hFH相互作用，这在活的肺炎球菌细胞上得到了证实。该抑制剂首次实现了对PspC-hFH相互作用的药理学干预。这种PPI抑制减少了肺炎球菌对上皮细胞的附着，也使D39菌株对调理作用重新敏感。重要的是，我们进一步设计了CCP9的共价变体，其以低纳摩尔效力实现了对PspC的长效抑制。总体而言，我们的结果展示了PPI抑制在对抗细菌感染方面的前景以及共价抑制剂的作用。
