| 名称 | TCA1 |
| 描述 | TCA1 (TCA 1) is a small molecule with activity against drug-resistant and persistent tuberculosis. |
| 细胞实验 | For kinetic killing assays, exponentially growing cultures of mycobacteria were diluted in fresh media to an OD600 of 0.1–0.2. Various drugs were added to the culture at the indicated concentrations. The number of cfus at the start of the experiment was estimated by plating appropriate dilutions of the culture onto 7H10 agar plates. The effect of drug was monitored by plating for cfus at the indicated time points. All experiments were carried out in triplicate. MICs were determined by a turbidity assay. Threefold serial dilutions in DMSO were prepared for each compound. Mtb cultures (OD = 0.04) were incubated with compounds at 37 °C for 5 d, and OD600 was determined with an Envision plate reader. All experiments were carried out in duplicate. For assays under starvation conditions, a log-phase growing Mtb culture was centrifuged, and the cell pellet was washed two times with PBS, resuspended in PBS with Tyloxapol (0.05%; OD = 0.3), and incubated with DMSO, TCA1 (7.5 μg/mL), and RIF (2 μg/mL). All experiments were carried out in triplicate. For intracellular macrophage assays, J744.1 murine macrophage cells were infected with Mtb at a multiplicity of infection (MOI) of 1:3 and incubated for 2 h at 37 °C. After washing the cell monolayer three times, 20 μM amikacin was added, and the culture was incubated for an additional 2 h to kill the remaining extracellular bacteria. Infected cells were then incubated in the presence of serial dilutions of compounds for 5 d. Cells were washed three times and lysed in each well; the lysate was transferred to a 96-well plate for serial dilution and then plated on 7H11 agar medium for cfu assays. |
| 动物实验 | Six- to eight-week-old female BALB/c mice were infected by aerosol with a low dose (～50 bacilli) of Mtb H37Rv. Infection dose was verified by plating the inoculum and the whole-lung homogenates onto 7H10 plates at 24 h postinfection. Treatment of BALB/c mice began at either 2 or 4 wk postinfection, with RIF (10 mg/kg) and INH (25 mg/kg) administered ad libitum in drinking water (changed one time every 2 d). TCA1 was administered by oral gavage one time daily for 5 d/wk at a dosage of either 40 or 100 mg/kg for the indicated durations. At predetermined time points or humane endpoints, animals were heavily sedated and euthanized, and tissues were collected for culture and pathology. Treatment efficacy was assessed on the basis of cfu in the lungs and spleen of treated mice compared with untreated controls and bacterial burden in these organs before treatment start. Organs were homogenized in PBS containing Tween-80 [0.05% (vol/vol)], and various dilutions were placed on 7H10 plates. Plates were incubated at 37 °C for 3 wk, and cfus on the various plates were recorded. |
| 体外活性 | TCA1对M. smegmatis、M. bovis bacillus Calmette–Guérin和Mtb的活性，在生物膜培养基中比在7H9培养基中高出20至150倍（分别为MIC50 = 0.03、0.04和0.01 μg/mL，相较于MIC50 = 4.5、3和0.19 μg/mL）。TCA1具有杀菌作用，在固体培养基中的MIC99值为2.1 μg/mL。 |
| 体内活性 | 经静脉给药后，TCA1显示了低清除率和稳定的分布体积，以及0.73小时的消除半衰期。口服给予20和50 mg/kg溶液制剂后，TCA1表现出高Cmax（分别为2,122和5,653 nM），中等的暴露度，口服生物利用度在19%至46%之间，以及1.8小时的半衰期。BALB/c小鼠被低剂量的Mtb H37Rv（约200个菌落）感染；感染后2周，用TCA1（40 mg/kg）治疗4周（每周5天，每天1次）。经过4周的TCA1治疗，肺中的cfu下降了0.5对数，脾脏中下降了1.5对数。 |
| 存储条件 | Powder: -20°C for 3 years | In solvent: -80°C for 1 year
Shipping with blue ice/Shipping at ambient temperature. |
| 溶解度 | DMSO : 60 mg/mL (159.82 mM), Sonication is recommended.
|
| 关键字 | tuberculosis | TCA1 | oral | Mycobacterium | MoeW | Inhibitor | inhibit | DprE1 | Bacterial |
| 相关产品 | Adipic dihydrazide | Levulinic acid | Doxycycline | Neomycin sulfate | Terbinafine hydrochloride | BES | Dimethyl sulfoxide | Sodium bicarbonate | Hyaluronic acid sodium (MW 20 kDa) | Sodium diacetate | Sulfamethoxazole sodium | D(+)-Raffinose pentahydrate |
| 相关库 | 经典已知活性库 | 已知活性化合物库 | 抗菌活性库 | 抗生素库 | 抗感染化合物库 | NO PAINS 化合物库 |
