Screening Discovery Platform, Institut Pasteur Korea, Seongnam, Gyeonggi, 13488, Republic of Korea.
Tuberculosis Research Laboratory, Institut Pasteur Korea, Seongnam, Gyeonggi, 13488, Republic of Korea.
Sci Rep. 2022 Apr 4;12(1):5635. doi: 10.1038/s41598-022-08209-w.
Para-aminosalicylic acid (PAS) is an antibiotic that was largely used for the multi-therapy of tuberculosis in the twentieth century. To try to overcome the inconvenience of its low efficacy and poor tolerance, we searched for novel chemical entities able to synergize with PAS using a combination screening against growing axenic Mycobacterium tuberculosis. The screening was performed at a sub-inhibitory concentration of PAS on a library of about 100,000 small molecules. Selected hit compounds were analyzed by dose-response and further probed with an intracellular macrophage assay. Scaffolds with potential additive effect with PAS are reported, opening interesting prospects for mechanism of action studies. We also report here evidence of a yet unknown bio-activation mechanism, involving activation of pyrido[1,2-a]pyrimidin-4-one (PP) derivatives through the Rv3087 protein.
对氨基水杨酸（PAS）是一种抗生素，在 20 世纪被广泛用于结核病的多疗法。为了克服其疗效低和耐受性差的不便，我们使用针对生长的无菌结核分枝杆菌的组合筛选来寻找能够与 PAS 协同作用的新型化学实体。筛选在 PAS 的亚抑制浓度下在大约 100,000 个小分子的库上进行。通过剂量反应选择命中化合物，并进一步用细胞内巨噬细胞测定法进行探测。报告了与 PAS 具有潜在相加作用的支架，为作用机制研究开辟了有趣的前景。我们还在此报告了一个未知的生物激活机制的证据，该机制涉及通过 Rv3087 蛋白激活吡啶并[1,2-a]嘧啶-4-酮（PP）衍生物。
