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.