Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
Drug Discovery and Development Centre (H3D), Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa.
ACS Infect Dis. 2023 Mar 10;9(3):706-715. doi: 10.1021/acsinfecdis.3c00012. Epub 2023 Feb 20.
The rise in drug-resistant tuberculosis has necessitated the search for alternative antibacterial treatments. Spiropyrimidinetriones (SPTs) represent an important new class of compounds that work through gyrase, the cytotoxic target of fluoroquinolone antibacterials. The present study analyzed the effects of a novel series of SPTs on the DNA cleavage activity of gyrase. H3D-005722 and related SPTs displayed high activity against gyrase and increased levels of enzyme-mediated double-stranded DNA breaks. The activities of these compounds were similar to those of the fluoroquinolones, moxifloxacin, and ciprofloxacin and greater than that of zoliflodacin, the most clinically advanced SPT. All the SPTs overcame the most common mutations in gyrase associated with fluoroquinolone resistance and, in most cases, were more active against the mutant enzymes than wild-type gyrase. Finally, the compounds displayed low activity against human topoisomerase IIα. These findings support the potential of novel SPT analogues as antitubercular drugs.
耐药结核病的增加促使人们寻找替代的抗菌治疗方法。螺吡喃并嘧啶酮（SPTs）是一类重要的新型化合物，通过拓扑异构酶 IV（gyrase）发挥作用，拓扑异构酶 IV 是氟喹诺酮类抗菌药物的细胞毒性靶标。本研究分析了一系列新型 SPT 对 gyrase 的 DNA 切割活性的影响。H3D-005722 和相关 SPT 对 gyrase 表现出高活性，并增加了酶介导的双链 DNA 断裂水平。这些化合物的活性与氟喹诺酮类药物莫西沙星和环丙沙星相似，且大于临床最先进的 SPT 唑利福定。所有 SPT 都克服了与氟喹诺酮类耐药相关的 gyrase 最常见的突变，并且在大多数情况下，对突变酶的活性大于对野生型 gyrase。最后，这些化合物对人拓扑异构酶 IIα 的活性较低。这些发现支持新型 SPT 类似物作为抗结核药物的潜力。
