ML267 free base is a blood-brain barrier permeable Antibacterial agent and bacterial phosphopantetheinyl transferase ( PPTase ) inhibitor, with an IC50 of 0.29 μM against Bacillus subtilis Sfp-PPTase and an IC50 of 8.1 μM against bacterial AcpS-PPTase. ML267 free base attenuates bacterial secondary metabolism, activity, and the production of Sfp-PPTase -dependent metabolites. ML267 free base inhibits the growth of Gram-positive bacteria, including Methicillin -resistant Staphylococcus aureus. ML267 free base is applicable to research related to bacterial infections, including methicillin-resistant Staphylococcus aureus infections [1] [2] [3].
In Vivo, ML267 free base fails to improve survival in a mouse model of MRSA sepsis[1]. ML267 free base (3-30 mg/kg; i.v., i.p.; single dose) achieves favorable systemic exposure and crosses the blood-brain barrier in healthy CD1 mice with no acute toxicity at tested doses[1]. ML267 free base (3-30 mg/kg; i.v., i.p.; single dose) exhibits favorable in vivo pharmacokinetic properties in male CD-1 mice, with 98.5% bioavailability after intraperitoneal administration at 30 mg/kg and a plasma-to-brain ratio of 2.1, and a half-life of 2.4 hours after intravenous administration at 3 mg/kg[3].
In Vitro, ML267 (free base) (3.6 nM-114 μM; 15 min pre-incubation, 30 min reaction) potently inhibits bacterial Sfp-PPTase with an IC50 of 0.290 μM and shows no activity against human PPTase at concentrations up to 114 μM[1]. ML267 (free base) (up to 8.1 μM; 15 min pre-incubation, 60 min reaction) inhibits bacterial AcpS-PPTase with an IC50 of 8.1 μM[1]. ML267 (free base) (0.4-100 μg/mL; 16-20 h, 4 h resazurin) exhibits bactericidal activity against Gram-positive bacterial strains including methicillin-resistant Staphylococcus aureus, with MICs ranging from 1.7 to 6.3 μg/mL, and no activity against Gram-negative bacteria or fungi[1]. ML267 (free base) (0.53-1.1 μg/mL; 28 h) dose-dependently attenuates Sfp-PPTase-dependent surfactin production in Bacillus subtilis OKB105 by 33-41% at sublethal concentrations, with minimal impact on bacterial growth[1]. ML267 (free base) potently inhibits bacterial Sfp-type PPTase (IC50 = 0.29 μM) and AcpS-type PPTase (IC50 = 8.1 μM), with no activity against the human PPTase ortholog[2]. ML267 (free base) (0.156-40 μM; 6 h) inhibits the growth of Bacillus subtilis ATCC 21332 with a MIC of 5.0 μM[2]. ML267 (free base) (serial dilutions; 15 min with enzyme, 30 min with substrate) potently inhibits Sfp phosphopantetheinyl transferase with an IC50 of 290 nM in a qHTS assay[3]. ML267 (free base) (serial dilutions; 48 h) exhibits no significant cytotoxicity against HepG2 human hepatocarcinoma cells, with an IC50 greater than 57 μM[3].
References:
[1]. Foley TL, et al. 4-(3-Chloro-5-(trifluoromethyl)pyridin-2-yl)-N-(4-methoxypyridin-2-yl)piperazine-1-carbothioamide (ML267), a potent inhibitor of bacterial phosphopantetheinyl transferase that attenuates secondary metabolism and thwarts bacterial growth. J Med Chem. 2014 Feb 13;57(3):1063-78.
[2]. Konno S, et al. A Chemoproteomics Approach to Investigate Phosphopantetheine Transferase Activity at the Cellular Level. Chembiochem. 2017;18(18):1855-1862.
[3]. Foley T L, et al. Discovery of ML 267 as a Novel Inhibitor of Pathogenic Sfp phosphopantetheinyl transferase (PPTase)[J]. Probe Reports from the NIH Molecular Libraries Program [Internet], 2013.
In Vivo, ML267 free base fails to improve survival in a mouse model of MRSA sepsis[1]. ML267 free base (3-30 mg/kg; i.v., i.p.; single dose) achieves favorable systemic exposure and crosses the blood-brain barrier in healthy CD1 mice with no acute toxicity at tested doses[1]. ML267 free base (3-30 mg/kg; i.v., i.p.; single dose) exhibits favorable in vivo pharmacokinetic properties in male CD-1 mice, with 98.5% bioavailability after intraperitoneal administration at 30 mg/kg and a plasma-to-brain ratio of 2.1, and a half-life of 2.4 hours after intravenous administration at 3 mg/kg[3].
In Vitro, ML267 (free base) (3.6 nM-114 μM; 15 min pre-incubation, 30 min reaction) potently inhibits bacterial Sfp-PPTase with an IC50 of 0.290 μM and shows no activity against human PPTase at concentrations up to 114 μM[1]. ML267 (free base) (up to 8.1 μM; 15 min pre-incubation, 60 min reaction) inhibits bacterial AcpS-PPTase with an IC50 of 8.1 μM[1]. ML267 (free base) (0.4-100 μg/mL; 16-20 h, 4 h resazurin) exhibits bactericidal activity against Gram-positive bacterial strains including methicillin-resistant Staphylococcus aureus, with MICs ranging from 1.7 to 6.3 μg/mL, and no activity against Gram-negative bacteria or fungi[1]. ML267 (free base) (0.53-1.1 μg/mL; 28 h) dose-dependently attenuates Sfp-PPTase-dependent surfactin production in Bacillus subtilis OKB105 by 33-41% at sublethal concentrations, with minimal impact on bacterial growth[1]. ML267 (free base) potently inhibits bacterial Sfp-type PPTase (IC50 = 0.29 μM) and AcpS-type PPTase (IC50 = 8.1 μM), with no activity against the human PPTase ortholog[2]. ML267 (free base) (0.156-40 μM; 6 h) inhibits the growth of Bacillus subtilis ATCC 21332 with a MIC of 5.0 μM[2]. ML267 (free base) (serial dilutions; 15 min with enzyme, 30 min with substrate) potently inhibits Sfp phosphopantetheinyl transferase with an IC50 of 290 nM in a qHTS assay[3]. ML267 (free base) (serial dilutions; 48 h) exhibits no significant cytotoxicity against HepG2 human hepatocarcinoma cells, with an IC50 greater than 57 μM[3].
References:
[1]. Foley TL, et al. 4-(3-Chloro-5-(trifluoromethyl)pyridin-2-yl)-N-(4-methoxypyridin-2-yl)piperazine-1-carbothioamide (ML267), a potent inhibitor of bacterial phosphopantetheinyl transferase that attenuates secondary metabolism and thwarts bacterial growth. J Med Chem. 2014 Feb 13;57(3):1063-78.
[2]. Konno S, et al. A Chemoproteomics Approach to Investigate Phosphopantetheine Transferase Activity at the Cellular Level. Chembiochem. 2017;18(18):1855-1862.
[3]. Foley T L, et al. Discovery of ML 267 as a Novel Inhibitor of Pathogenic Sfp phosphopantetheinyl transferase (PPTase)[J]. Probe Reports from the NIH Molecular Libraries Program [Internet], 2013.