Drug-resistant infections have become a serious threat to human health in the past two decades. Global Antimicrobial Surveillance (GLASS) in January 2018 reported widespread antibiotic resistance among 1.5 million people infected with bacteria across 22 countries. According to prominent economist Jim O'Neil, antimicrobial resistance is estimated to kill ∼10 million people affected by microorganisms each year by 2050. Even though multiple therapeutics are now available to treat the infections, more and more bacterial strains have acquired resistance to these treatments through various techniques. Moreover, the decrease in the pipeline of antibacterial medicines under clinical development has become a significant problem. In this scenario, the development of novel antibiotics that act on untapped pathways is necessary to combat the bacterial infections. Isoprenoid H (IspH) synthetase has become an attractive antibacterial target as there is no human homologue. IspH is an enzyme involved in methyl-d-erythritol phosphate (MEP) pathway of isoprenoid synthesis and is conserved in gram-negative bacteria, mycobacteria, and apicomplexans. Since, IspH is a novel therapeutic target, explorations are only just beginning, and despite the progress made in this area, no single IspH inhibitor is available in the market for therapeutic use. In this article, we have repurposed 35 immune boosters against IspH enzyme using methods such as extra-precision docking and Molecular Mechanics Generalized Born Surface Area (MMGBSA). Among them, 4′-fluorouridine was found to be active because of its glide score and significant binding affinity with IspH enzyme. Furthermore, this study requires more in vitro, in vivo, and molecular dynamics studies to support our findings.

中文翻译：

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双效免疫抗生素：免疫增强剂对类异戊二烯 H 酶抗菌功效的计算研究

在过去的二十年中，耐药性感染已成为对人类健康的严重威胁。2018 年 1 月，全球抗菌素监测 (GLASS) 报告称，在 22 个国家/地区的 150 万感染细菌的人中存在广泛的抗生素耐药性。根据著名经济学家吉姆·奥尼尔（Jim O'Neil）的说法，到 2050 年，估计每年有 1000 万人受到微生物的耐药性而死亡。尽管现在有多种治疗方法可以治疗感染，但越来越多的细菌菌株已经对这些治疗产生了耐药性通过各种技术。此外，临床开发中的抗菌药物管线减少已成为一个重大问题。在这种情况下，开发作用于未开发途径的新型抗生素对于对抗细菌感染是必要的。由于没有人类同源物，类异戊二烯 H (IspH) 合成酶已成为有吸引力的抗菌靶标。IspH是一种参与甲基化的酶类异戊二烯合成的d-赤藓糖醇磷酸 (MEP) 途径，在革兰氏阴性菌、分枝杆菌和顶复门菌中是保守的。由于 IspH 是一种新的治疗靶点，探索才刚刚开始，尽管在该领域取得了进展，但市场上没有单一的 IspH 抑制剂可用于治疗用途。在本文中，我们使用超精密对接和分子力学广义出生表面积 (MMGBSA) 等方法重新利用了 35 种针对 IspH 酶的免疫增强剂。其中，4'-氟尿苷因其滑动分数和与 IspH 酶的显着结合亲和力而被发现具有活性。此外，这项研究需要更多的体外、体内和分子动力学研究来支持我们的发现。