Abstract:
Gyrase and topoisomerase IV are the cellular targets for fluoroquinolones, a critically important class of antibacterial agents used to treat a broad spectrum of human infections. Unfortunately, the clinical efficacy of the fluoroquinolones has been curtailed by the emergence of target-mediated resistance. This is especially true for Neisseria gonorrhoeae, the causative pathogen of the sexually transmitted infection gonorrhea. Spiropyrimidinetriones (SPTs), a new class of antibacterials, were developed to combat the growing antibacterial resistance crisis. Zoliflodacin is the most clinically advanced SPT and displays efficacy against uncomplicated urogenital gonorrhea in human trials. Like fluoroquinolones, the primary target of zoliflodacin in N. gonorrhoeae is gyrase, and topoisomerase IV is a secondary target. Because unbalanced gyrase/topoisomerase IV targeting has facilitated the evolution of fluoroquinolone-resistant bacteria, it is important to understand the underlying basis for the differential targeting of zoliflodacin in N. gonorrhoeae. Therefore, we assessed the effects of this SPT on the catalytic and DNA cleavage activities of N. gonorrhoeae gyrase and topoisomerase IV. In all reactions examined, zoliflodacin displayed higher potency against gyrase than topoisomerase IV. Moreover, zoliflodacin generated more DNA cleavage and formed more stable enzyme-cleaved DNA-SPT complexes with gyrase. The SPT also maintained higher activity against fluoroquinolone-resistant gyrase than topoisomerase IV. Finally, when compared to zoliflodacin, the novel SPT H3D-005722 induced more balanced double-stranded DNA cleavage with gyrase and topoisomerase IV from N. gonorrhoeae, Escherichia coli, and Bacillus anthracis. This finding suggests that further development of the SPT class could yield compounds with a more balanced targeting against clinically important bacterial infections.
摘要:
旋转酶和拓扑异构酶IV是氟喹诺酮类药物的细胞靶标,用于治疗广谱人类感染的一类至关重要的抗菌剂。不幸的是,氟喹诺酮类药物的临床疗效因靶介导耐药的出现而受到削弱.淋病奈瑟菌尤其如此,性传播感染淋病的病原体。螺嘧啶二酮(SPT),一类新的抗菌药物,是为了对抗日益增长的抗菌耐药性危机而开发的。佐利福达星是临床上最先进的SPT,在人体试验中对不复杂的泌尿生殖道淋病具有疗效。像氟喹诺酮类药物,淋病奈瑟菌中佐利他星的主要作用靶点是促旋酶,拓扑异构酶IV是次要靶标。由于不平衡的促旋酶/拓扑异构酶IV靶向促进了氟喹诺酮耐药细菌的进化,重要的是要了解佐利福定在淋病奈瑟菌中的差异靶向的基础。因此,我们评估了该SPT对淋病奈瑟菌促旋酶和拓扑异构酶IV的催化和DNA裂解活性的影响。在检查的所有反应中,与拓扑异构酶IV相比,佐利法沙星对促旋酶的效力更高。此外,佐利福定产生更多的DNA裂解,并与促旋酶形成更稳定的酶裂解DNA-SPT复合物。与拓扑异构酶IV相比,SPT对氟喹诺酮抗性促旋酶也保持更高的活性。最后,与佐利福妥相比,新型SPTH3D-005722用促旋酶和拓扑异构酶IV诱导更平衡的双链DNA裂解。大肠杆菌,和炭疽芽孢杆菌.该发现表明SPT类的进一步发展可以产生针对临床上重要的细菌感染具有更平衡靶向的化合物。