Abstract：
Polyamines are small cationic molecules that have been linked to various cellular processes including replication, translation, stress response and recently, capsule regulation in Streptococcus pneumoniae (Spn, pneumococcus). Pneumococcal-associated diseases such as pneumonia, meningitis, and sepsis are some of the leading causes of death worldwide and capsule remains the principal virulence factor of this versatile pathogen. α-Difluoromethyl-ornithine (DFMO) is an irreversible inhibitor of the polyamine biosynthesis pathway catalyzed by ornithine decarboxylase and has a long history in modulating cell growth, polyamine levels, and disease outcomes in eukaryotic systems. Recent evidence shows that DFMO can also target arginine decarboxylation. Interestingly, DFMO-treated cells often escape polyamine depletion via increased polyamine uptake from extracellular sources. Here, we examined the potential capsule-crippling ability of DFMO and the possible synergistic effects of the polyamine transport inhibitor, AMXT 1501, on pneumococci. We characterized the changes in pneumococcal metabolites in response to DFMO and AMXT 1501, and also measured the impact of DFMO on amino acid decarboxylase activities. Our findings show that DFMO inhibited pneumococcal polyamine and capsule biosynthesis as well as decarboxylase activities, albeit, at a high concentration. AMXT 1501 at physiologically relevant concentration could inhibit both polyamine and capsule biosynthesis, however, in a serotype-dependent manner. In summary, this study demonstrates the utility of targeting polyamine biosynthesis and transport for pneumococcal capsule inhibition. Since targeting capsule biosynthesis is a promising way for the eradication of the diverse and pathogenic pneumococcal strains, future work will identify small molecules similar to DFMO/AMXT 1501, which act in a serotype-independent manner.
摘要：
多胺是阳离子小分子，已与各种细胞过程，包括复制，翻译,应激反应和最近，肺炎链球菌（Spn，肺炎球菌）。肺炎等肺炎球菌相关疾病,脑膜炎,和败血症是世界范围内死亡的一些主要原因，胶囊仍然是这种多功能病原体的主要毒力因子。α-二氟甲基-鸟氨酸（DFMO）是鸟氨酸脱羧酶催化的多胺生物合成途径的不可逆抑制剂，在调节细胞生长方面有着悠久的历史，多胺水平，和真核系统中的疾病结果。最近的证据表明，DFMO也可以靶向精氨酸脱羧。有趣的是,DFMO处理的细胞通常通过从细胞外来源吸收的多胺增加而逃避多胺消耗。这里,我们检查了DFMO的潜在胶囊致残能力和多胺转运抑制剂可能的协同作用，AMXT1501，关于肺炎球菌。我们表征了响应DFMO和AMXT1501的肺炎球菌代谢物的变化，并测量了DFMO对氨基酸脱羧酶活性的影响。我们的研究结果表明，DFMO抑制肺炎球菌多胺和胶囊生物合成以及脱羧酶活性，虽然,在高浓度。生理相关浓度的AMXT1501可以抑制多胺和胶囊生物合成，然而,以血清型依赖的方式。总之,这项研究证明了靶向多胺生物合成和转运对肺炎球菌胶囊抑制的实用性。由于靶向胶囊生物合成是根除多样化和致病性肺炎球菌菌株的一种有希望的方法，未来的工作将鉴定类似于DFMO/AMXT1501的小分子,这些小分子以不依赖于血清型的方式起作用.
