Synergy Screening Identifies a Compound That Selectively Enhances the Antibacterial Activity of Nitric Oxide
Synergy Screening Identifies a Compound That Selectively Enhances the Antibacterial Activity of Nitric Oxide
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DOI：
10.3389/fbioe.2020.01001
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发表时间：
2020-08-25
影响因子：
5.7
通讯作者：
Brynildsen, Mark P.
中科院分区：
文献类型：
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作者：
Chou, Wen Kang;Vaikunthan, Mathini;Brynildsen, Mark P.
抗生素耐药性对全球健康构成严重威胁。为了加强抗感染的武器库，许多新的治疗策略，以打击细菌感染正在探索。其中，靶向毒力重要通路的抗毒力疗法备受关注。一氧化氮（NO）防御系统已被确定为各种细菌的发病机制的关键，使它们成为一个有吸引力的治疗靶点。在这项研究中，我们进行了化学筛选，以确定抑制剂的NO解毒inEscherichia coli。我们发现，2-巯基苯并噻唑（2-MBT）可以有效地抑制NO的细胞解毒，达到类似于在含氧条件下遗传去除Hmp（主要解毒酶）的效果的抑制水平。进一步的分析表明，在NO的存在下，2-MBT损害Hmp的催化和Hmp和其他蛋白质的合成，而在其不存在的情况下，有最小的扰动生长和蛋白质合成。此外，通过对2-MBT构效关系的研究，我们发现2-MBT中的两个硫原子都是其抑制NO解毒的关键。有趣的是，当使用缺少苯环的2-巯基噻唑（2-MT）时，观察到不同的生物活性，尽管它们也是NO依赖性的。具体而言，2-MT仍然可以抑制NO解毒，虽然它不干扰Hmp催化;相反，它是一个更强的蛋白质合成抑制剂，它降低了hmp的转录水平，这是没有观察到与2-MBT。总体而言，这些结果为进一步探索2-MBT和2-MT的治疗应用提供了坚实的基础。
Antibiotic resistance poses a serious threat to global health. To reinforce the anti-infective arsenal, many novel therapeutic strategies to fight bacterial infections are being explored. Among them, anti-virulence therapies, which target pathways important for virulence, have attracted much attention. Nitric oxide (NO) defense systems have been identified as critical for the pathogenesis of various bacteria, making them an appealing therapeutic target. In this study, we performed chemical screens to identify inhibitors of NO detoxification inEscherichia coli. We found that 2-mercaptobenzothiazole (2-MBT) can potently inhibit cellular detoxification of NO, achieving a level of inhibition that resembled the effect of genetically removing Hmp, the dominant detoxification enzyme under oxygenated conditions. Further analysis revealed that in the presence of NO, 2-MBT impaired the catalysis of Hmp and synthesis of Hmp and other proteins, whereas in its absence there were minimal perturbations to growth and protein synthesis. In addition, by studying the structure-activity relationship of 2-MBT, we found that both sulfur atoms in 2-MBT were vital for its inhibition of NO detoxification. Interestingly, when 2-mercaptothiazole (2-MT), which lacked the benzene ring, was used, differing biological activities were observed, although they too were NO dependent. Specifically, 2-MT could still prohibit NO detoxification, though it did not interfere with Hmp catalysis; rather, it was a stronger inhibitor of protein synthesis and it reduced the transcript levels ofhmp, which was not observed with 2-MBT. Overall, these results provide a strong foundation for further exploration of 2-MBT and 2-MT for therapeutic applications.