Department of Mycobacteriology, Leprosy Research Center, National Institute of Infectious Diseases, Tokyo, Japan.
Department of Pathology, Field of Oncology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
PLoS One. 2022 Oct 6;17(10):e0274742. doi: 10.1371/journal.pone.0274742. eCollection 2022.
Buruli ulcer (BU) is a skin disease caused by Mycobacterium ulcerans infection that requires long-term antibiotic treatment and/or surgical excision. In this study, we investigated the therapeutic efficacy of the rifamycin derivative, rifalazil (RLZ) (also known as KRM-1648), in an advanced M. ulcerans infection model. Six-week-old female BALB/c mice were infected with 3.25 x 104 colony-forming units (CFU) of M. ulcerans subcutaneously into the bilateral hind footpads. At 33 days post-infection, when the footpads exhibited significant redness and swelling, mice were treated orally with 5 or 10 mg/kg of RLZ for up to 15 weeks. Mice were followed for an additional 15 weeks following treatment cessation. Untreated mice exhibited a progressive increase in footpad redness, swelling, and erosion over time, and all untreated mice reached to endpoint within 5-8 weeks post-bacterial injection. In the RLZ-treated mice, footpad redness and swelling and general condition improved or completely healed, and no recurrence occurred following treatment cessation. After 3 weeks of treatment, the CFU counts from the footpads of recovered RLZ-treated mice showed a 104 decrease compared with those of untreated mice. We observed a further reduction in CFU counts to the detection limit following 6 to 15 weeks of treatment, which did not increase 15 weeks after discontinuing the treatment. Histopathologically, bacteria in the treated mice became fragmented one week after RLZ-treatment. At the final point of the experiment, all the treated mice (5mg/kg/day; n = 6, 10mg/kg/day; n = 7) survived and had no signs of M. ulcerans infection. These results indicate that the rifamycin analogue, RLZ, is efficacious in the treatment of an advanced M. ulcerans infection mouse model.
布鲁里溃疡（BU）是由溃疡分枝杆菌感染引起的皮肤疾病，需要长期使用抗生素治疗和/或手术切除。在这项研究中，我们研究了利福霉素衍生物利福拉齐（RLZ）（也称为 KRM-1648）在晚期溃疡分枝杆菌感染模型中的治疗效果。将 3.25x104 个菌落形成单位（CFU）的溃疡分枝杆菌皮下接种到双侧后足垫，感染 6 周龄雌性 BALB/c 小鼠。感染后 33 天，当足垫出现明显的红肿和肿胀时，用 5 或 10mg/kg RLZ 进行口服治疗，持续 15 周。在治疗停止后，继续对小鼠进行 15 周的随访。未治疗的小鼠表现出随着时间的推移，足垫红肿、肿胀和侵蚀的逐渐增加，所有未治疗的小鼠在细菌注射后 5-8 周内达到终点。在 RLZ 治疗的小鼠中，足垫红肿、肿胀和一般状况得到改善或完全治愈，并且在治疗停止后没有复发。在治疗 3 周后，与未治疗的小鼠相比，恢复 RLZ 治疗的小鼠的足垫 CFU 计数下降了 104。在 6 至 15 周的治疗后，我们观察到 CFU 计数进一步减少到检测限以下，并且在停止治疗 15 周后没有增加。组织病理学检查显示，RLZ 治疗一周后，治疗小鼠的细菌出现片段化。在实验的最后一点，所有接受治疗的小鼠（5mg/kg/天；n=6，10mg/kg/天；n=7）存活且无溃疡分枝杆菌感染的迹象。这些结果表明，利福霉素类似物 RLZ 在治疗晚期溃疡分枝杆菌感染小鼠模型中是有效的。
