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首页> 外文期刊>Antimicrobial agents and chemotherapy. >Simple fibroblast-based assay for screening of new antimicrobial drugs against Mycobacterium tuberculosis.
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Simple fibroblast-based assay for screening of new antimicrobial drugs against Mycobacterium tuberculosis.

机译：基于成纤维细胞的简单测定方法，用于筛选抗结核分枝杆菌的新抗菌药物。

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In this study, we propose a simple and reproducible host-cell-based assay for the screening of antimycobacterial drugs that is suitable for drug discovery. The method evaluates both antimycobacterial activity of the drugs and their cytotoxicity to host cells. The basis of this simple fibroblast-based assay (SFA) is that cells of human lung fibroblast cell line MRC-5, which are highly sensitive to mycobacterial cytotoxicity, are killed by virulent Mycobacterium tuberculosis strain H(37)Rv bacilli in response to the viability of bacilli. Clinically used antimycobacterial drugs inhibited the mycobacterial cytotoxicity to MRC-5 cells in a dose-dependent manner. MICs of isoniazid, streptomycin, rifampin, and ethambutol determined by this SFA (0.428, 1.816, 0.013, and 3.465 microg/ml, respectively) were within 1 log of MICs determined by the broth dilution test (BDT) using Middlebrook 7H9 medium. The MIC of pyrazinamide, which exhibits bactericidal activity only at a high dose by BDT (1,231 microg/ml at pH 6.6 and 492 microg/ml at pH 5.8), was 3.847 microg/ml in the modified method of SFA. On the other hand, sodium azide, a toxic agent for both mammalian cells and bacteria, exhibited cytotoxicity to fibroblasts at a dose lower than that required to inhibit mycobacterial growth. Thus, this fibroblast-based method enabled us to evaluate both antibacterial activity of drugs and their cytotoxicity to human cells within a short period of time.
机译：在这项研究中，我们提出了一种简单且可重现的基于宿主细胞的测定方法，用于筛选适合药物发现的抗分枝杆菌药物。该方法评估了药物的抗分枝杆菌活性及其对宿主细胞的细胞毒性。这种简单的基于成纤维细胞的测定（SFA）的基础是，对分枝杆菌细胞毒性高度敏感的人肺成纤维细胞MRC-5细胞被有毒的结核分枝杆菌菌株H（37）Rv杆菌杀死，细菌的生存力。临床上使用的抗分枝杆菌药物以剂量依赖的方式抑制了分枝杆菌对MRC-5细胞的细胞毒性。通过该SFA测定的异烟肼，链霉素，利福平和乙胺丁醇的MIC（分别为0.428、1.816、0.013和3.465 microg / ml）在使用Middlebrook 7H9培养基通过肉汤稀释试验（BDT）测定的MIC的1 log之内。在改良的SFA方法中，吡嗪酰胺的MIC仅在高剂量下通过BDT表现出杀菌活性（pH 6.6为1,231 microg / ml，pH 5.8为492 microg / ml），其MIC为3.847 microg / ml。另一方面，对于哺乳动物细胞和细菌均具有毒性的叠氮化钠对成纤维细胞的细胞毒性低于抑制分枝杆菌生长所需的剂量。因此，这种基于成纤维细胞的方法使我们能够在短时间内评估药物的抗菌活性及其对人细胞的细胞毒性。

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