Mitton-Fry Mark J, Cummings Jason E, Lu Yanran, Armenia Jillian F, Byl Jo Ann W, Oviatt Alexandria A, Bauman Allison A, Robertson Gregory T, Osheroff Neil, Slayden Richard A
Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210, United States.
Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado 80523, United States.
ACS Infect Dis. 2025 Feb 14;11(2):474-482. doi: 10.1021/acsinfecdis.4c00743. Epub 2025 Jan 10.
Developing new classes of drugs that are active against infections caused by is a priority for treating and managing this deadly disease. Here, we describe screening a small library of 20 DNA gyrase inhibitors and identifying new lead compounds. Three structurally diverse analogues were identified with minimal inhibitory concentrations of 0.125 μg/mL against both drug-susceptible and drug-resistant strains of . These lead compounds also demonstrated antitubercular activity in ex vivo studies using infected THP-1 macrophages with minimal cytotoxicity in THP-1, HeLa, and HepG2 cells (IC ≥ 128 μg/mL). The molecular target of the lead compounds was validated through biochemical studies of select analogues with purified gyrase and the generation of resistant mutants. The lead compounds were assessed in combination with bedaquiline and pretomanid to determine the clinical potential, and the select lead () demonstrated in vivo efficacy in an acute model of TB infection in mice, reducing the lung bacterial burden by approximately 3 log versus untreated control mice. The advancement of DNA gyrase inhibitors expands the field of innovative therapies for tuberculosis and may offer an alternative to fluoroquinolones in future therapeutic regimens.
开发对由……引起的感染有效的新型药物类别是治疗和控制这种致命疾病的优先事项。在此，我们描述了对一个包含20种DNA促旋酶抑制剂的小型文库进行筛选并鉴定出新的先导化合物。鉴定出了三种结构不同的类似物，它们对……的药物敏感菌株和耐药菌株的最低抑菌浓度均为0.125μg/mL。这些先导化合物在使用感染的THP-1巨噬细胞的体外研究中也表现出抗结核活性，在THP-1、HeLa和HepG2细胞中具有最小细胞毒性（IC≥128μg/mL）。通过对选定类似物与纯化的……促旋酶进行生化研究以及产生抗性突变体，验证了先导化合物的分子靶点。将先导化合物与贝达喹啉和pretomanid联合评估以确定其临床潜力，选定的先导化合物（……）在小鼠结核感染急性模型中显示出体内疗效，与未治疗的对照小鼠相比，肺部细菌负荷降低了约3个对数。DNA促旋酶抑制剂的进展扩大了结核病创新疗法的领域，并可能在未来的治疗方案中为氟喹诺酮类药物提供替代选择。
