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).

中文翻译：

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三种碳青霉烯类、氯法齐明和硝唑尼特的抗结核活性使用一种新的人类结核病离体表型药物敏感性模型

我们评估了结核 (TB) 肉芽肿的新型生理 3-D 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，包括目前用于治疗的一种；和硝唑尼特，一种可能具有结核活性的抗寄生虫化合物（所有选择都是因为常规药物敏感性存在问题）。从健康供体收集的 PBMC 被分离并感染结核分枝杆菌H37Rv lux（即荧光素酶）。用受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。将克拉维酸盐添加到每个碳青霉烯中以抑制 β-内酰胺酶。结核分枝杆菌(MTB) 杀灭效力是剂量依赖性的。氯法齐明是最有效的抑制 MTB 生长的药物，浓度为 2 mg/L，在两个测试浓度下均具有良好的杀灭活性。它是唯一一种在测试的最低浓度下就能杀死细菌的药物。碳青霉烯类显示出适度的初始活性，在孵育的第 10 天左右丧失，而克拉维酸盐没有增加杀灭活性。在测试的碳青霉烯类药物中，替比培南杀灭 MTB 的效率最高，尽管浓度很高。硝唑尼特仅在当前剂量无法达到的浓度下有效（尽管这可能部分是与广泛的蛋白质结合相关的假象）。