CHIR-090是一种强效、缓慢、紧密结合的LpxC脱乙酰酶抑制剂，CHIR-090与大肠杆菌LpxC结合的Ki值为4.0nM。
Cas No.:728865-23-4
Sample solution is provided at 25 µL, 10mM.
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CHIR-090 is a potent, slow, and tight-binding LpxC deacetylase inhibitor, with a Ki value of 4.0nM for binding to Escherichia coli LpxC[1-2]. By specifically inhibiting LpxC, CHIR-090 blocks lipid A biosynthesis, thereby exerting excellent antibiotic activity, and can be used in research targeting Gram-negative bacteria[3-4].
In vitro, CHIR-090 (4μg/ml) was used to treat Pseudomonas aeruginosa, which screened for various resistant mutants, including overexpression mutants of the efflux pump systems MexAB-OprM, MexCD-OprJ, and MexEF-OprN, as well as amino acid substitution mutations in the target LpxC (LpxC L18V) or LpxC overexpression caused by ribosomal binding site mutations[5]. When CHIR-090 (0.1-100μg/ml) was applied to the Burkholderia cepacia complex, CHIR-090 significantly reduced the survival of B. multivorans but showed no inhibitory activity against some strains of B. cenocepacia[6].
In vivo, CHIR-090 (4mg/kg) was administered intraperitoneally to a mouse model implanted with Pseudomonas aeruginosa PAO1 biofilm (single dose). CHIR-090 monotherapy reduced the bacterial load in implants and spleens by approximately 2log10, while combination therapy with polymyxin (10mg/kg) further reduced the bacterial load by 4log10 and inhibited bacterial dissemination to the spleen[7].
References:
[1] Barb AW, Jiang L, Raetz CR, et al. Structure of the deacetylase LpxC bound to the antibiotic CHIR-090: Time-dependent inhibition and specificity in ligand binding. Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18433-8.
[2] Cole KE, Gattis SG, Angell HD, et al. Structure of the metal-dependent deacetylase LpxC from Yersinia enterocolitica complexed with the potent inhibitor CHIR-090 . Biochemistry. 2011 Jan 18;50(2):258-65.
[3] Amudala S, Sumit, Aidhen IS. LpxC inhibition: Potential and opportunities with carbohydrate scaffolds. Carbohydr Res. 2024 Mar;537:109057.
[4] Niu Z, Lei P, Wang Y, et al. Small molecule LpxC inhibitors against gram-negative bacteria: Advances and future perspectives. Eur J Med Chem. 2023 May 5;253:115326.
[5] Caughlan RE, Jones AK, Delucia AM, et al. Mechanisms decreasing in vitro susceptibility to the LpxC inhibitor CHIR-090 in the gram-negative pathogen Pseudomonas aeruginosa. Antimicrob Agents Chemother. 2012 Jan;56(1):17-27.
[6] Bodewits K, Raetz CR, Govan JR, et al. Antimicrobial activity of CHIR-090, an inhibitor of lipopolysaccharide biosynthesis, against the Burkholderia cepacia complex. Antimicrob Agents Chemother. 2010 Aug;54(8):3531-3.
[7] Tan JH, Vidaillac C, Yam JKH, et al. In Vitro and In Vivo Efficacy of an LpxC Inhibitor, CHIR-090, Alone or Combined with Colistin against Pseudomonas aeruginosa Biofilm. Antimicrob Agents Chemother. 2017 Jun 27;61(7):e02223-16.
CHIR-090是一种强效、缓慢、紧密结合的LpxC脱乙酰酶抑制剂，CHIR-090与大肠杆菌LpxC结合的Ki值为4.0nM[1-2]。CHIR-090通过特异性抑制LpxC，阻断脂质A的生物合成，从而发挥优异的抗生素活性，CHIR-090可用于针对革兰氏阴性菌的相关研究[3-4]。
在体外，CHIR-090（4μg/ml）处理铜绿假单胞菌（Pseudomonas aeruginosa）可筛选出多种耐药突变株，包括外排泵系统MexAB-OprM、MexCD-OprJ和MexEF-OprN的过表达突变体，以及靶点LpxC的氨基酸置换突变（LpxC L18V）或核糖体结合位点突变导致的LpxC过表达[5]。CHIR-090（0.1-100μg/ml）处理伯克霍尔德菌复合体（Burkholderia cepacia complex），CHIR-090显著降低B. multivorans的存活，而对B. cenocepacia的部分菌株无抑制活性[6]。
在体内，CHIR-090（4mg/kg）腹腔注射处理植入铜绿假单胞菌（Pseudomonas aeruginosa）PAO1生物膜的小鼠模型（单次给药），CHIR-090单药治疗使植入物和脾脏的细菌载量降低约2log10，而与多黏菌素（10mg/kg）联用可进一步将细菌载量降低4log10，并抑制细菌向脾脏扩散[7]。
| Cell experiment [1]: | |
Cell lines | Pseudomonas aeruginosa (Gram-negative pathogen), Burkholderia cepacia complex strains (including B. multivorans, B. cenocepacia, and other clinical isolates). |
Preparation Method | Bacterial strains were cultured in LB broth or Mueller-Hinton broth under standard aerobic conditions at 37°C. Susceptibility testing was performed using broth micro dilution(CHIR-090; 0.1-100μg/ml) methods. |
Reaction Conditions | 0.1-100μg/ml; 18-24h |
Applications | CHIR-090 significantly inhibited growth of B. multivorans and B. dolosa (e.g., MIC =0.1–6.25µg/mL for B. multivorans strains), but showed no activity against smooth-LPS B. cenocepacia strains (K56-2). The compound’s efficacy correlated with LpxC inhibition, disrupting outer membrane integrity via lipid A biosynthesis blockade. |
| Animal experiment [2]: | |
Animal models | BALB/c mice |
Preparation Method | Mice were subcutaneously inoculated with Pseudomonas aeruginosa PAO1 biofilm-producing strain encapsulated in agar beads (approximately 106CFU per implant) at the dorsal subcutaneous tissue. Treatments began 24h post-infection (CHIR-090; 4mg/kg/dose; intraperitoneal injection; Polymyxin B; 10mg/kg/dose; intraperitoneal injection). |
Dosage form | 4mg/kg/dose; i.p.; single injection |
Applications | CHIR-090 monotherapy significantly reduced bacterial burden in implants and spleens by approximately 2-log10CFU compared to untreated controls. Combination therapy with polymyxin B enhanced efficacy, achieving up to 4-log10CFU reduction in bacterial load and preventing systemic dissemination to the spleen. These findings demonstrate CHIR-090's therapeutic potential in treating Gram-negative biofilm-associated infections in vivo. |
References: | |
| Cas No. | 728865-23-4 | SDF | |
| 别名 | CHIR 090;CHIR090 | ||
| 化学名 | N-[(2S,3R)-3-hydroxy-1-(hydroxyamino)-1-oxobutan-2-yl]-4-[2-[4-(morpholin-4-ylmethyl)phenyl]ethynyl]benzamide | ||
| Canonical SMILES | CC(C(C(=O)NO)NC(=O)C1=CC=C(C=C1)C#CC2=CC=C(C=C2)CN3CCOCC3)O | ||
| 分子式 | C24H27N3O5 | 分子量 | 437.49 |
| 溶解度 | ≥ 21.85 mg/mL in DMSO | 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 | 2.2858 mL | 11.4288 mL | 22.8577 mL |
| 5 mM | 457.2 μL | 2.2858 mL | 4.5715 mL |
| 10 mM | 228.6 μL | 1.1429 mL | 2.2858 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。
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