PHARMACOLOGY OF CERTAIN ANTIMICROBIAL N¹,N⁵-SUBSTITUTED BIGUANIDES

¹ The Veterans Administration Hospital, the Department of Physiology and Pharmacology and of Pathology, Duke Medical Center, Durham, North Carolina
² Department of Chemistry, Duke University, Durham, North Carolina

Six N¹,N⁵-substituted biguanides were shown to inhibit growth of certain pathogenic yeasts at concentrations from less than 1.0 to 10 µg/ml. The reported high activity against certain gram-positive bacteria was confirmed. Chelation of certam divalent cations was shown to occur, but this single property was considered insufficient to account for all pharmacological activities investigated. Yeast glycolysis was inhibited by all six compounds, but significant reversal by divalent cation could be demonstrated with only two inhibitors. Lecithin completely reversed the inhibition, with an apparent binding of the biguanide with the phospholipid. The dose-response of yeast glycolysis to each compound showed a standard distribution of susceptibility to inhibition, indicating an all-or-none effect on each cell without an individual graded response. The possibility that the mechanism of action may be related to an alteration of the cytoplasmic membrane was strengthened by the finding that each compound was hemolytic to human erythrocytes at low concentrations, with a standard distribution of resistances in the red cell population, and that yeast cells rapidly lost purines and pyrimidines in the presence of each compound. Pyruvic carboxylase was inhibited by four of the six compounds, but no definite evidence was found that the mechanism was by chelation. A metal-free enzyme, urease, was not affected.