Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States.
Holistic Drug Discovery and Development (H3D) Centre, University of Cape Town, Rondebosch 7701, South Africa.
ACS Infect Dis. 2024 Aug 9;10(8):3071-3082. doi: 10.1021/acsinfecdis.4c00438. Epub 2024 Jul 31.
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 , 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 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 . Therefore, we assessed the effects of this SPT on the catalytic and DNA cleavage activities of 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 , , and . This finding suggests that further development of the SPT class could yield compounds with a more balanced targeting against clinically important bacterial infections.
回旋酶和拓扑异构酶 IV 是氟喹诺酮类药物的细胞靶标，氟喹诺酮类药物是一类重要的抗菌药物，用于治疗广泛的人类感染。不幸的是，氟喹诺酮类药物的临床疗效受到了靶标介导耐药性的限制。这在治疗性传播感染淋病的病原体 时尤其如此。螺吡喃并嘧啶酮类（SPTs）是一类新的抗菌药物，旨在对抗日益严重的抗菌药物耐药性危机。唑利福啶是最具临床进展的 SPT，在人体试验中显示出对单纯性泌尿生殖系淋病的疗效。与氟喹诺酮类药物一样，唑利福啶在 中的主要靶标是回旋酶，拓扑异构酶 IV 是次要靶标。由于回旋酶/拓扑异构酶 IV 靶向的不平衡促进了氟喹诺酮类耐药菌的进化，因此了解唑利福啶在 中差异化靶向的基础非常重要。因此，我们评估了该 SPT 对 回旋酶和拓扑异构酶 IV 的催化和 DNA 切割活性的影响。在所有检查的反应中，唑利福啶对回旋酶的活性均高于拓扑异构酶 IV。此外，唑利福啶产生了更多的 DNA 切割，并与回旋酶形成了更稳定的酶切割 DNA-SPT 复合物。该 SPT 对氟喹诺酮类耐药回旋酶的活性也高于拓扑异构酶 IV。最后，与唑利福啶相比，新型 SPT H3D-005722 诱导了来自 、 和 的回旋酶和拓扑异构酶 IV 更平衡的双链 DNA 切割。这一发现表明，进一步开发 SPT 类药物可能会产生针对临床重要细菌感染具有更平衡靶向性的化合物。
