Anti-Tuberculosis Activity of Three Carbapenems, Clofazimine and Nitazoxanide Using a Novel Ex Vivo Phenotypic Drug Susceptibility Model of Human Tuberculosis.
Anti-Tuberculosis Activity of Three Carbapenems, Clofazimine and Nitazoxanide Using a Novel Ex Vivo Phenotypic Drug Susceptibility Model of Human Tuberculosis.
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DOI：
10.3390/antibiotics11101274
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发表时间：
2022-09-20
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我们评估了结核病 (TB) 肉芽肿的新型生理 3D 生物电喷雾模型，以测试已知抗结核药物氯法齐明的活性；三种具有潜在活性的碳青霉烯类，其中一种目前用于治疗；硝唑尼特，一种可能具有结核活性的抗寄生虫化合物（所有选择的常规药物敏感性都是有问题的）。分离从健康捐献者收集的 PBMC，并用结核分枝杆菌 H37Rv lux（即荧光素酶）感染。被感染的细胞产生微球；添加抗微生物化合物并监测细菌发光至少 21 天。将克拉维酸添加到每种碳青霉烯中以抑制β-内酰胺酶。结核分枝杆菌 (MTB) 杀灭效果呈剂量依赖性。氯法齐明是抑制 MTB 生长最有效的药物，浓度为 2 mg/L，在两个测试浓度下均具有良好的杀灭活性。它是唯一能在最低测试浓度下杀死细菌的药物。碳青霉烯类药物表现出适度的初始活性，但在孵育第 10 天左右就消失了，并且克拉维酸并没有增加杀灭活性。在测试的碳青霉烯类中，替比培南杀灭 MTB 的效率最高，尽管浓度较高。硝唑尼特仅在当前剂量无法达到的浓度下才有效（尽管这可能部分是与广泛的蛋白质结合有关的人为因素）。
We evaluated a novel physiological 3-D bioelectrospray model of the tuberculosis (TB) granuloma to test the activity of a known anti-TB drug, clofazimine; three carbapenems with potential activity, including one currently used in therapy; and nitazoxanide, an anti-parasitic compound with possible TB activity (all chosen as conventional drug susceptibility was problematical). PBMCs collected from healthy donors were isolated and infected with M. tuberculosis H37Rv lux (i.e., luciferase). Microspheres were generated with the infected cells; the anti-microbial compounds were added and bacterial luminescence was monitored for at least 21 days. Clavulanate was added to each carbapenem to inhibit beta-lactamases. M. tuberculosis (MTB) killing efficacy was dose dependent. Clofazimine was the most effective drug inhibiting MTB growth at 2 mg/L with good killing activity at both concentrations tested. It was the only drug that killed bacteria at the lowest concentration tested. Carbapenems showed modest initial activity that was lost at around day 10 of incubation and clavulanate did not increase killing activity. Of the carbapenems tested, tebipenem was the most efficient in killing MTB, albeit at a high concentration. Nitazoxanide was effective only at concentrations not achievable with current dosing (although this might partly have been an artefact related to extensive protein binding).