Targocil
目录号 : GC32077
Targocil可用作磷壁酸(WTA)生物合成的抑菌抑制剂，可抑制甲氧西林敏感金黄色葡萄球菌(MSSA）和耐甲氧西林金黄色葡萄球菌(MRSA)的生长，对于MRSA和MSSA的MIC90值都为2μg/mL。
Cas No.:1200443-21-5
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Cell experiment: | Log-phase strains MG2375, MG2389, Newman, and MW2 are collected and adjusted to a concentration of 2×108 CFU/mL. After the treatment of bacterial cultures with Targocil at 10×MIC for 1 h, the cells are diluted 1:1,000 in fresh medium and then incubated and plated at the appropriate time points for viability determination. The postantibiotic effect (PAE) is calculated by the standard equation T-C, where T is the time required for the CFU count in the test culture to increase 10-fold above the count observed immediately after drug removal, and C is the time required for the count of the untreated control to increase 10-fold under the same conditions[1]. |
References: [1]. Suzuki T, et al. In vitro antimicrobial activity of wall teichoic acid biosynthesis inhibitors against Staphylococcus aureus isolates. Antimicrob Agents Chemother. 2011 Feb;55(2):767-74. | |
Targocil functions as a bacteriostatic inhibitor of wall teichoic acid (WTA) biosynthesis which can inhibit the growth of methicillin-susceptible S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA) with MIC90s of 2 μg/ mL for both MRSA and MSSA.
MICs of Targocil against S. aureus strains Newman, MW2, MG2375, and MG2389 are 1 μg/mL for all strains. Targocil shows excellent activity against S. aureus isolates from suspected cases of bacterial keratitis, including both MSSA and MRSA isolates, with MICs that range from 1 to 2 μg/ mL. Targocil, a derivative of 1835F03, exhibits better activity against all keratitis isolates than the original lead compound, 1835F03. Bovine serum exhibits a detectable but moderate inhibitory effect on the in vitro antimicrobial activities of both 1835F03 and Targocil, increasing the MICs of both by 4- to 8-fold. Compare to the vehicle alone, Targocil at 5 μg/mL exhibits little toxicity for HCECs, even after 24 h of exposure. However, 40 μg/mL Targocil shows toxicity at all time points tested. Targocil at levels equal to 10×MIC in vitro readily inhibits growth of Newman and MG2375 in the presence of HCECs[1]
[1]. Suzuki T, et al. In vitro antimicrobial activity of wall teichoic acid biosynthesis inhibitors against Staphylococcus aureus isolates. Antimicrob Agents Chemother. 2011 Feb;55(2):767-74.
| Cas No. | 1200443-21-5 | SDF | |
| Canonical SMILES | COC1=CC2=C(C=C1OC)C(N(CC)CC)=NC3=C(S(=O)(C4=CC=C(Cl)C=C4)=O)N=NN32 | ||
| 分子式 | C21H22ClN5O4S | 分子量 | 475.95 |
| 溶解度 | DMSO : 33.33 mg/mL (70.03 mM);Water : < 0.1 mg/mL (insoluble) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.1011 mL | 10.5053 mL | 21.0106 mL |
| 5 mM | 0.4202 mL | 2.1011 mL | 4.2021 mL |
| 10 mM | 0.2101 mL | 1.0505 mL | 2.1011 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Bacillus anthracis Responds to Targocil-Induced Envelope Damage through EdsRS Activation of Cardiolipin Synthesis
mBio 2020 Mar 31;11(2):e03375-19.PMID:32234818DOI:10.1128/mBio.03375-19.
Bacillus anthracis is a spore-forming bacterium that causes devastating infections and has been used as a bioterror agent. This pathogen can survive hostile environments through the signaling activity of two-component systems, which couple environmental sensing with transcriptional activation to initiate a coordinated response to stress. In this work, we describe the identification of a two-component system, EdsRS, which mediates the B. anthracis response to the antimicrobial compound Targocil. Targocil is a cell envelope-targeting compound that is toxic to B. anthracis at high concentrations. Exposure to Targocil causes damage to the cellular barrier and activates EdsRS to induce expression of a previously uncharacterized cardiolipin synthase, which we have named ClsT. Both EdsRS and ClsT are required for protection against targocil-dependent damage. Induction of clsT by EdsRS during Targocil treatment results in an increase in cardiolipin levels, which protects B. anthracis from envelope damage. Together, these results reveal that a two-component system signaling response to an envelope-targeting antimicrobial induces production of a phospholipid associated with stabilization of the membrane. Cardiolipin is then used to repair envelope damage and promote B. anthracis viability.IMPORTANCE Compromising the integrity of the bacterial cell barrier is a common action of antimicrobials. Targocil is an antimicrobial that is active against the bacterial envelope. We hypothesized that Bacillus anthracis, a potential weapon of bioterror, senses and responds to Targocil to alleviate targocil-dependent cell damage. Here, we show that Targocil treatment increases the permeability of the cellular envelope and is particularly toxic to B. anthracis spores during outgrowth. In vegetative cells, two-component system signaling through EdsRS is activated by Targocil. This results in an increase in the production of cardiolipin via a cardiolipin synthase, ClsT, which restores the loss of barrier function, thereby reducing the effectiveness of Targocil. By elucidating the B. anthracis response to Targocil, we have uncovered an intrinsic mechanism that this pathogen employs to resist toxicity and have revealed therapeutic targets that are important for bacterial defense against structural damage.
Exposure of Staphylococcus aureus to Targocil Blocks Translocation of the Major Autolysin Atl across the Membrane, Resulting in a Significant Decrease in Autolysis
Antimicrob Agents Chemother 2018 Jun 26;62(7):e00323-18.PMID:29735561DOI:10.1128/AAC.00323-18.
Peptidoglycan (PG) and wall teichoic acid (WTA) are the major staphylococcal cell wall components, and WTA biosynthesis has recently been explored for drug development. Targocil is a novel agent that targets the TarG subunit of the WTA translocase (TarGH) that transports WTA across the membrane to the wall. Previously we showed that Targocil treatment of a methicillin-susceptible Staphylococcus aureus strain led to a rapid shut down of cellular autolysis. Targocil II, which targets the TarH subunit of TarGH, also resulted in a drastic decrease in autolysis. Here, we address the mechanism of targocil-mediated decreased autolysis. The mechanism is WTA dependent since Targocil treatment decreased autolysis in methicillin-resistant strains but not in a WTA-deficient mutant. Similar to cellular autolysis, autolysin-retaining crude cell walls isolated from targocil-treated cells had vastly decreased autolytic activity compared to those from untreated cells. Purified cell walls from control and targocil-treated cells, which lack autolytic activity, were similarly susceptible to lysozyme and lysostaphin and had similar O-acetyl contents, indicating that Targocil treatment did not grossly alter PG structure and chemistry. Purified cell walls from targocil-treated cells were highly susceptible to autolysin extracts, supporting the notion that Targocil treatment led to decreased autolysin in the crude cell walls. Quantitative real-time PCR analysis revealed that the decrease in autolysis in the targocil-exposed cells was not due to transcriptional repression of the autolysin genes atl, lytM, lytN, and sle1 Zymographic analysis of peptidoglycan hydrolase profiles showed a deficiency of cell surface autolysins in targocil-treated cells but higher activity in cell membrane fractions. Here, we propose that the untranslocated WTA molecules in the targocil-exposed cells sequester Atl at the membrane, resulting in significantly decreased autolysis.
A new target for Staphylococcus aureus associated with keratitis
Cornea 2011 Oct;30 Suppl 1:S34-40.PMID:21912228DOI:10.1097/ICO.0b013e3182282100.
Staphylococcus aureus is a leading cause of keratitis, with an increased number of isolates exhibiting antibiotic resistance. Therefore, we need to understand the present situation regarding drug-resistant S. aureus in the ocular site. It has been shown that 35% of S. aureus isolates from ocular sites are methicillin-resistant Staphylococcus aureus (MRSA). MRSA isolates from ocular sites have a high rate of multiple mutations and high levels of resistance against fluoroquinolones. Wall teichoic acids (WTAs) are major polyanionic polymers in the cell wall of S. aureus and are likely to be important in the pathogenesis of eye infection. A new compound, Targocil, was recently shown to function as a bacteriostatic inhibitor of WTA biosynthesis in S. aureus. The minimum inhibitory concentration (MIC) at which 90% of the keratitis isolates are inhibited (MIC90) by Targocil was 2 μg/mL for both MRSA and methicillin-sensitive Staphylococcus aureus. Targocil exhibited little toxicity at concentrations near the MIC, with increased toxicity at higher concentrations and longer exposure times. Targocil inhibited intracellular bacteria in the presence of human corneal epithelial cells to a greater extent than vancomycin. Targocil-resistant strains exhibited a significantly reduced ability to adhere to human corneal epithelial cells (P < 0.001). The WTA biosynthesis pathway of S. aureus appears to be a viable target for preventing keratitis caused by strains of this bacterium.
New Structural Templates for Clinically Validated and Novel Targets in Antimicrobial Drug Research and Development
Curr Top Microbiol Immunol 2016;398:365-417.PMID:27704270DOI:10.1007/82_2016_501.
The development of bacterial resistance against current antibiotic drugs necessitates a continuous renewal of the arsenal of efficacious drugs. This imperative has not been met by the output of antibiotic research and development of the past decades for various reasons, including the declining efforts of large pharma companies in this area. Moreover, the majority of novel antibiotics are chemical derivatives of existing structures that represent mostly step innovations, implying that the available chemical space may be exhausted. This review negates this impression by showcasing recent achievements in lead finding and optimization of antibiotics that have novel or unexplored chemical structures. Not surprisingly, many of the novel structural templates like teixobactins, lysocin, griselimycin, or the albicidin/cystobactamid pair were discovered from natural sources. Additional compounds were obtained from the screening of synthetic libraries and chemical synthesis, including the gyrase-inhibiting NTBI's and spiropyrimidinetrione, the tarocin and Targocil inhibitors of wall teichoic acid synthesis, or the boronates and diazabicyclo[3.2.1]octane as novel β-lactamase inhibitors. A motif that is common to most clinically validated antibiotics is that they address hotspots in complex biosynthetic machineries, whose functioning is essential for the bacterial cell. Therefore, an introduction to the biological targets-cell wall synthesis, topoisomerases, the DNA sliding clamp, and membrane-bound electron transport-is given for each of the leads presented here.
In vitro antimicrobial activity of wall teichoic acid biosynthesis inhibitors against Staphylococcus aureus isolates
Antimicrob Agents Chemother 2011 Feb;55(2):767-74.PMID:21098254DOI:10.1128/AAC.00879-10.
Staphylococcus aureus is the leading cause of invasive and superficial human infections, is increasingly antibiotic resistant, and is therefore the target for the development of new antimicrobials. Compounds (1835F03 and Targocil) were recently shown to function as bacteriostatic inhibitors of wall teichoic acid (WTA) biosynthesis in S. aureus. To assess the value of targeting WTA biosynthesis in human infection, it was therefore of interest to verify the involvement of WTA in bacterial binding to human corneal epithelial cells (HCECs) and to assess the activities of inhibitors of WTA biosynthesis against clinical isolates of methicillin-susceptible S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA) from cases of human keratitis. The 1835F03 MIC(90)s were 8 μg/ml for MSSA keratitis isolates and >32 μg/ml for MRSA keratitis isolates. The MIC(90) for the analog of 1835F03, Targocil, was 2 μg/ml for both MRSA and MSSA. Targocil exhibited little toxicity at concentrations near the MIC, with increased toxicity occurring at higher concentrations and with longer exposure times. Targocil activity was moderately sensitive to the presence of serum, but it inhibited extracellular and intracellular bacteria in the presence of HCECs better than vancomycin. Targocil-resistant strains exhibited a significantly reduced ability to adhere to HCECs.