CHIR-090

- Overview
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    Background
    
    CHIR-090 is a very potent, low, tight-binding inhibitor of LpxC with Ki value of 4.0 nM [1].LpxC is a zinc-dependent amidase and present in almost all Gram-negative bacteria. LpxC is a promising target for the development of novel antibiotic substances against multigrug-resistant Gram-negative bacteria [2].CHIR-090 is a potent LpxC inhibitor and has a different selectivity with the reported LpxC inhibitor L-161. When tested with Escherichia coli LpxC, administration of CHIR-090 showed tight inhibition with Ki value of 4.0 nM, Ki*=0.5 nM, K5=1.9/min and K6=0.18/min [1]. In bacterial P.aeruginosa efflux pupm mutants, CHIR-090 treatment showed inhibition function on MexAB-Oprm, MexCD-OprJ and MexEF-OprN [2]. CHIR-090 showed remarkable antibiotic activity against both E.coli and P.aeruginosa by inhibiting LpxC orthologs at low nM concentrations [3].In E.coli W3110RL with R.legumunosarum lpxC replacement of E.coli lpxC, CHIR-090 (1 to 10 μg/ml) treatment had no effect on strain growth on LB agar plates while wild-type cells stopped growing after about 2 h in the presence of 1 μg/ml CHIR-090 [1].
    
    [1].Barb, A.W., et al., Inhibition of lipid A biosynthesis as the primary mechanism of CHIR-090 antibiotic activity in Escherichia coli. Biochemistry, 2007. 46(12): p. 3793-802.
    [2].Barb, A.W. and P. Zhou, Mechanism and inhibition of LpxC: an essential zinc-dependent deacetylase of bacterial lipid A synthesis. Curr Pharm Biotechnol, 2008. 9(1): p. 9-15.
    [3].McClerren, A.L., et al., A slow, tight-binding inhibitor of the zinc-dependent deacetylase LpxC of lipid A biosynthesis with antibiotic activity comparable to ciprofloxacin. Biochemistry, 2005. 44(50): p. 16574-83.
- Properties
  - Alternative Name
    
    CHIR 090;CHIR090; N-[(2S,3R)-3-hydroxy-1-(hydroxyamino)-1-oxobutan-2-yl]-4-[2-[4-(morpholin-4-ylmethyl)phenyl]ethynyl]benzamide
    
    CAS Number
    
    728865-23-4
    
    Molecular Formula
    
    C24H27N3O5
    
    Molecular Weight
    
    437.49
    
    Appearance
    
    A solid
    
    Purity
    
    99.37%
    
    Solubility
    
    ≥21.85 mg/mL in DMSO; insoluble in EtOH; insoluble in H2O
    
    Storage
    
    Store at -20°C
    
    * For Research Use Only
- Reference
  - 1. Justin J. Zik, Sung Hwan Yoon, et al. "Caulobacter lipid A is conditionally dispensable in the absence of fur and in the presence of anionic sphingolipids." Cell Rep. 2022 May 31;39(9):110888. PMID: 35649364
    2. Basta DW, Angeles-Albores D, et al. "Heat-shock proteases promote survival of Pseudomonas aeruginosa during growth arrest." Proc Natl Acad Sci U S A. 2020;117(8):4358–4367. PMID: 32029587
    3. David W. Basta. "Genetic Determinants of Growth Arrest Survival in the Bacterial Pathogen Pseudomonas aeruginosa and the Role of Proteases." CALIFORNIA INSTITUTE OF TECHNOLOGY.2019.

CHIR-090

Background

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