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Synergism in the folate pathway

R J Harvey

    Reviews of Infectious Diseases
    |March 1, 1982
    PubMed
    Summary

    Synergism between drug inhibitors can arise from metabolic pathway configurations. The cyclic nature of the folate pathway explains the synergistic effect observed with trimethoprim and sulfamethoxazole.

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    Area of Science:

    • Biochemistry
    • Pharmacology
    • Systems Biology

    Background:

    • Drug synergism, where combined drugs enhance therapeutic effect, is crucial in pharmacology.
    • Metabolic pathways exhibit complex kinetics influencing drug interactions.
    • The folate pathway is essential for microbial survival and a target for antibiotics.

    Purpose of the Study:

    • To investigate the mechanistic basis of synergism between trimethoprim and sulfamethoxazole.
    • To elucidate the role of metabolic pathway configuration in drug synergism.

    Main Methods:

    • Analysis of enzyme kinetics within the folate metabolic pathway.
    • Computational modeling of metabolic flux and drug interactions.
    • Review of existing literature on trimethoprim and sulfamethoxazole mechanisms.

    Main Results:

    • Synergism between inhibitors of metabolic enzymes can be predicted by pathway structure.
    • The cyclic configuration of the folate pathway is directly responsible for the observed synergism.
    • Nonlinear enzyme kinetics contribute to the synergistic effect.

    Conclusions:

    • The cyclic nature of the folate pathway dictates the synergistic interaction between trimethoprim and sulfamethoxazole.
    • Understanding pathway topology is key to predicting and exploiting drug synergism.
    • This principle applies broadly to inhibitors targeting enzymes in cyclic metabolic pathways.

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