Triazine inhibits Toxoplasma gondii tachyzoites in vitro and in vivo

E J Mui, D Jacobus, W K Milhous, G Schiehser, H H Hsu, C W Roberts, M J Kirisits, R McLeod

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

The triazine WR99210 [4,6-diamino-1,2-dihydro-2,2-dimethyl-l-(2,4,5-trichlorophenoxypropyloxy)-1,3,5 triazinel inhibits Toxoplasma gondii in vitro at nanomolar levels (P < 0.05). The 50% inhibitory concentration IC50) was approximately 50 nM. It is a potent inhibitor in vitro and is also effective in vivo. Administration of WR99210 parenterally (i.e., intraperitoneally) reduced the mean number of RH strain tachyzoites present in peritoneal fluid substantially 4 days after intraperitoneal infection of mice. There was a mean of approximately 35 million parasites in control mice as contrasted with approximately 2 million parasites in mice treated with 1.25 mg WR99210/kg of body weight in a representative experiment (P < 0.05). In addition the prodrug PS-15 N'-[3-(2,4, 5-trichlorophenoxy)propyloxyl-N9-(I-methylethyl) imidocarbonimidicdiamide is converted to 4,6-diamino-1,2-dihydro-2,2-dimethyl-l-(2,4,5-trichlorophenoxypropyloxy)-1,3,5 triazine in vivo when the prodrug is administered orally. PS-15 administered by gavage also reduced intraperitoneal RH strain T. gondii tachyzoite numbers. WR99210 has high efficacy and relatively low toxicity because of its substantial effect on T. gondii dihydrofolate reductase (DHFR) but not the mammalian host DHFR. Amino acid sequences of T. gondii, Plasmodium falciparum, and Homo sapiens DHFRs were compared. It is of interest that of the DHFR amino acids considered to be interacting with WR99210 in P. falciparum within interatomic distances within 3 to 5 1, four of eight were shared with T. grondii DHFR. H. sapiens also shared four amino acids thought to be interacting with WR99210. Efficacy of intraperitoneal administration of VVR99210 and peroral administration of PS-15 demonstrate the potential usefulness of this class of compounds in treatment of toxoplasmosis administered either parenterally or perorally. The recent development program for this class of antimicrobials as antimalarials makes our proof of principle of improved efficacy of triazines (compared with the gold standard treatment, pyrimethamine) against T. gondii especially promising.

LanguageEnglish
Pages3463-3467
Number of pages5
JournalAntimicrobial Agents and Chemotherapy
Volume49
Issue number8
DOIs
Publication statusPublished - Aug 2005

Fingerprint

Triazines
Toxoplasma
Tetrahydrofolate Dehydrogenase
Prodrugs
Plasmodium falciparum
Inhibitory Concentration 50
Communicable Disease Control
Amino Acids
Pyrimethamine
Ascitic Fluid
Toxoplasmosis
Antimalarials
Amino Acid Sequence
Parasites
Body Weight
In Vitro Techniques
Infection
PS 15

Keywords

  • dihydrofolate reductase
  • plasmodium falciparum
  • Eantifolate resistance
  • pyrimethamine
  • cycloguanil
  • malarial
  • WR99210
  • antimalarial
  • combination
  • analogs

Cite this

Mui, E J ; Jacobus, D ; Milhous, W K ; Schiehser, G ; Hsu, H H ; Roberts, C W ; Kirisits, M J ; McLeod, R . / Triazine inhibits Toxoplasma gondii tachyzoites in vitro and in vivo. In: Antimicrobial Agents and Chemotherapy . 2005 ; Vol. 49, No. 8. pp. 3463-3467.
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Triazine inhibits Toxoplasma gondii tachyzoites in vitro and in vivo. / Mui, E J ; Jacobus, D ; Milhous, W K ; Schiehser, G ; Hsu, H H ; Roberts, C W ; Kirisits, M J ; McLeod, R .

In: Antimicrobial Agents and Chemotherapy , Vol. 49, No. 8, 08.2005, p. 3463-3467.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Triazine inhibits Toxoplasma gondii tachyzoites in vitro and in vivo

AU - Mui, E J

AU - Jacobus, D

AU - Milhous, W K

AU - Schiehser, G

AU - Hsu, H H

AU - Roberts, C W

AU - Kirisits, M J

AU - McLeod, R

PY - 2005/8

Y1 - 2005/8

N2 - The triazine WR99210 [4,6-diamino-1,2-dihydro-2,2-dimethyl-l-(2,4,5-trichlorophenoxypropyloxy)-1,3,5 triazinel inhibits Toxoplasma gondii in vitro at nanomolar levels (P < 0.05). The 50% inhibitory concentration IC50) was approximately 50 nM. It is a potent inhibitor in vitro and is also effective in vivo. Administration of WR99210 parenterally (i.e., intraperitoneally) reduced the mean number of RH strain tachyzoites present in peritoneal fluid substantially 4 days after intraperitoneal infection of mice. There was a mean of approximately 35 million parasites in control mice as contrasted with approximately 2 million parasites in mice treated with 1.25 mg WR99210/kg of body weight in a representative experiment (P < 0.05). In addition the prodrug PS-15 N'-[3-(2,4, 5-trichlorophenoxy)propyloxyl-N9-(I-methylethyl) imidocarbonimidicdiamide is converted to 4,6-diamino-1,2-dihydro-2,2-dimethyl-l-(2,4,5-trichlorophenoxypropyloxy)-1,3,5 triazine in vivo when the prodrug is administered orally. PS-15 administered by gavage also reduced intraperitoneal RH strain T. gondii tachyzoite numbers. WR99210 has high efficacy and relatively low toxicity because of its substantial effect on T. gondii dihydrofolate reductase (DHFR) but not the mammalian host DHFR. Amino acid sequences of T. gondii, Plasmodium falciparum, and Homo sapiens DHFRs were compared. It is of interest that of the DHFR amino acids considered to be interacting with WR99210 in P. falciparum within interatomic distances within 3 to 5 1, four of eight were shared with T. grondii DHFR. H. sapiens also shared four amino acids thought to be interacting with WR99210. Efficacy of intraperitoneal administration of VVR99210 and peroral administration of PS-15 demonstrate the potential usefulness of this class of compounds in treatment of toxoplasmosis administered either parenterally or perorally. The recent development program for this class of antimicrobials as antimalarials makes our proof of principle of improved efficacy of triazines (compared with the gold standard treatment, pyrimethamine) against T. gondii especially promising.

AB - The triazine WR99210 [4,6-diamino-1,2-dihydro-2,2-dimethyl-l-(2,4,5-trichlorophenoxypropyloxy)-1,3,5 triazinel inhibits Toxoplasma gondii in vitro at nanomolar levels (P < 0.05). The 50% inhibitory concentration IC50) was approximately 50 nM. It is a potent inhibitor in vitro and is also effective in vivo. Administration of WR99210 parenterally (i.e., intraperitoneally) reduced the mean number of RH strain tachyzoites present in peritoneal fluid substantially 4 days after intraperitoneal infection of mice. There was a mean of approximately 35 million parasites in control mice as contrasted with approximately 2 million parasites in mice treated with 1.25 mg WR99210/kg of body weight in a representative experiment (P < 0.05). In addition the prodrug PS-15 N'-[3-(2,4, 5-trichlorophenoxy)propyloxyl-N9-(I-methylethyl) imidocarbonimidicdiamide is converted to 4,6-diamino-1,2-dihydro-2,2-dimethyl-l-(2,4,5-trichlorophenoxypropyloxy)-1,3,5 triazine in vivo when the prodrug is administered orally. PS-15 administered by gavage also reduced intraperitoneal RH strain T. gondii tachyzoite numbers. WR99210 has high efficacy and relatively low toxicity because of its substantial effect on T. gondii dihydrofolate reductase (DHFR) but not the mammalian host DHFR. Amino acid sequences of T. gondii, Plasmodium falciparum, and Homo sapiens DHFRs were compared. It is of interest that of the DHFR amino acids considered to be interacting with WR99210 in P. falciparum within interatomic distances within 3 to 5 1, four of eight were shared with T. grondii DHFR. H. sapiens also shared four amino acids thought to be interacting with WR99210. Efficacy of intraperitoneal administration of VVR99210 and peroral administration of PS-15 demonstrate the potential usefulness of this class of compounds in treatment of toxoplasmosis administered either parenterally or perorally. The recent development program for this class of antimicrobials as antimalarials makes our proof of principle of improved efficacy of triazines (compared with the gold standard treatment, pyrimethamine) against T. gondii especially promising.

KW - dihydrofolate reductase

KW - plasmodium falciparum

KW - Eantifolate resistance

KW - pyrimethamine

KW - cycloguanil

KW - malarial

KW - WR99210

KW - antimalarial

KW - combination

KW - analogs

U2 - 10.1128/AAC.49.8.3463-3467.2005

DO - 10.1128/AAC.49.8.3463-3467.2005

M3 - Article

VL - 49

SP - 3463

EP - 3467

JO - Antimicrobial Agents and Chemotherapy

T2 - Antimicrobial Agents and Chemotherapy

JF - Antimicrobial Agents and Chemotherapy

SN - 0066-4804

IS - 8

ER -