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]。