Trimethoprim is a bacteriostatic antibiotic inhibiting dihydrofolate reductase (DHFR) enzyme activity. Trimethoprim selectively and reversibly inhibits bacterial DHFR, blocks the conversion of dihydrofolate to tetrahydrofolate, and interferes with bacterial nucleic acid and protein biosynthesis to exert antibacterial effects. Trimethoprim has antibacterial activity against susceptible Gram-positive aerobic cocci and Gram-negative aerobic bacilli such as Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae, Enterobacter species and Staphylococcus saprophyticus. Trimethoprim is often used in combination with sulphamethoxazole to enhance antibacterial effects. Trimethoprim can be used for research and treatment of urinary tract infections, traveler's diarrhea, acute exacerbations of chronic bronchitis and Pneumocystis jirovecii pneumonia[1-4].
In vitro, treatment of peripheral blood lymphocytes with 25-50μg/mL Trimethoprim for 24-48 hours increased micronucleus frequency. Treatment of F2408 and 5RP7 cells with 5-200μM Trimethoprim for 24-72 hours inhibited cell proliferation and decreased mitochondrial activity[5]. Treatment of HCT116, RKO, DLD1, MCF7, 4T1, SUM159 and PyMT cells with 0.1-4mM Trimethoprim for 48 hours reduced cell viability and induced G1 phase arrest, downregulated cyclin D1, CDK4, CDK6 and phospho-Rb protein expression, decreased Snail protein level and promoted ubiquitination degradation, weakened Snail binding to CBP/p300 and Snail acetylation, elevated Snail phosphorylation level, increased E-cadherin and decreased vimentin, N-cadherin and fibronectin expression, and inhibited cell migration[6]. Treatment of foreskin fibroblasts co-cultured with Toxoplasma gondii 2F strain with 46μM Trimethoprim for 5 days inhibited tachyzoite growth[7].
In vivo, feeding white mice intraperitoneally inoculated with Toxoplasma gondii RH strain with food containing 2mg Trimethoprim and 1mg sulphamethoxazole for 20 days prolonged survival days of infected mice[8]. Intravenous injection of 25mg/kg Trimethoprim into Sprague-Dawley rats via jugular vein 15 minutes before intravenous injection of 1mg/kg emtricitabine decreased emtricitabine clearance, prolonged emtricitabine elimination half-life, increased apparent volume of distribution, and decreased renal excretion rate of emtricitabine[9]. Administration of 35mg/kg-70mg/kg Trimethoprim via drinking water to Swiss Webster mice intraperitoneally inoculated with Toxoplasma gondii RH strain for 13 days failed to eradicate Toxoplasma and did not improve mouse survival[10].
References:
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[2] Rich G, Mee B. Trimethoprim. Med J Aust. 1985 Mar 18;142(6):350-2.
[3] Brogden RN, Carmine AA, Heel RC, et al. Trimethoprim: a review of its antibacterial activity, pharmacokinetics and therapeutic use in urinary tract infections. Drugs. 1982 Jun;23(6):405-30.
[4] Long MJC, Pan Y, Lin HC, et al. Cell Compatible Trimethoprim-Decorated Iron Oxide Nanoparticles Bind Dihydrofolate Reductase for Magnetically Modulating Focal Adhesion of Mammalian Cells. J Am Chem Soc. 2011 Jun 10;133(26):10006-10009.
[5] Guzel Bayülken D, Bostancioglu R B, Koparal A T, et al. Assessment of in vitro cytotoxic and genotoxic activities of some trimethoprim conjugates. Cytotechnology. 2018 Jun;70(3):1051-1059.
[6] Ren BX, Li Y, Li HM, et al. The antibiotic drug trimethoprim suppresses tumour growth and metastasis via targeting Snail. Br J Pharmacol. 2022 May;179(11):2659-2677.
[7] Hencken CP, Jones-Brando L, Bordon C, et al. Thiazole, Oxadiazole, and Carboxamide Derivatives of Artemisinin are Highly Selective and Potent Inhibitors of Toxoplasma gondii. J Med Chem. 2010 May 13;53(9):3594-3601.
[8] Sander J, Midtvedt T. The effect of trimethoprim on acute experimental toxoplasmosis in mice. Acta Pathol Microbiol Scand B. 1970;78(6):664-668.
[9] Nakatani-Freshwater T, Taft DR. Renal Excretion of Emtricitabine II. Effect of Trimethoprim on Emtricitabine Excretion: In Vitro and In Vivo Studies. J Pharm Sci. 2008 Dec;97(12):5411-5420.
[10] Dumas JL, Pizzolato G, Pechère JC. Evaluation of trimethoprim and sulphamethoxazole as monotherapy or in combination in the management of toxoplasmosis in murine models. Int J Antimicrob Agents. 1999 Jan;13(1):35-39.