Mode of Action of 6-Cyclohexyl-l-hydroxy-4-methyl-2(1H)-pyridone Ethanolamine Salt (Hoe 296)

Abstract

Mode of action studies were made with Hoe 296, a new synthetic antimycotic, mainly in Candida albicans. The specific parameters examined included possible effects on (i) osmotic fragility, (ii) respiration, (iii) uptake and incorporation of radioactive leucine and adenine, and (iv) leakage or efflux of intracellular K⁺ and other materials. As a result, fungitoxic activity of Hoe 296 appears to be attributed to inhibition of uptake of precursors of macromolecular syntheses from the medium. Uptake and accumulation of leucine in the internal pool of starved cells was more susceptible to the drug than subsequent incorporation into proteins. Hoe 296 was also effective in altering the cell permeability, but greater drug concentrations were required to induce appreciable leakage of cellular constituents, such as 260 nm-absorbing materials, folin-positive substances and potassium ions, from the cells. Osmotic fragility or endogenous respiration was virtually insensitive to the drug. Partial inhibition by relatively high concentrations of Hoe 296 of the respiratory activity of yeast cells or mitochondria therefrom with exogenous substrates can be explained by decreased uptake of the substrates from the medium.

Toward Repurposing Ciclopirox as an Antibiotic against Drug-Resistant Acinetobacter baumannii, Escherichia coli, and Klebsiella pneumoniae

“…Studies in C. albicans have shown that ciclopirox alters the structure of cell membranes [17], [49], [50]. Indeed, 97% of ciclopirox administered to C. albicans was bound to cell membranes and organelles, with very little drug in the cytoplasm [50].…”

Ciclopirox Olamine Treatment Affects the Expression Pattern ofCandida albicansGenes Encoding Virulence Factors, Iron Metabolism Proteins, and Drug Resistance Factors

“…Another feature that influences the clinical potency of the drug is its steep dose-response curve (16). Most of the studies dealing with the mode of action of this drug were published approximately 20 years ago, at the time that ciclopirox olamine was synthesized and introduced into clinical therapy (16,17,23,33,40,49). When the drug became more frequently used, the results of many investigations about its efficacy and comparisons of its clinical effectiveness with those of other antimicrobial agents were published (25); however, the primary mode of action was rarely investigated.…”

“…More than 97% of the accumulated drug is bound largely irreversibly to different cell structures and organelles such as the cell membrane, cell wall, mitochondria, microsomes, and ribosomes, while only small amounts are found in the cytosolic fraction. The drug is neither metabolized nor degraded (49). Furthermore, it was demonstrated that ciclopirox olamine causes inhibition of protein, RNA, and DNA synthesis in growing fungal cells, possibly by blocking the uptake of precursors of the macromolecules or by blocking the uptake of essential ions such as potassium ions and phosphates (33).…”

Treatment and Prophylaxis of Seborrheic Dermatitis of the Scalp With Antipityrosporal 1% Ciclopirox Shampoo

“…[10][11][12] Unlike the imidazoles and allylamines, which inhibit synthesis of fungal cell walls, ciclopirox complexes polyvalent cations, thus inhibiting metal-dependent enzymes including those responsible for peroxide degradation in the fungal cell. 13 There is some evidence of antibacterial and antiinflammatory activity. 11,14 The potent antipityrosporal effects of ciclopirox combined with its tolerability and lack of toxic effects make it an ideal alternative to existing antifungal agents both for treatment and prophylaxis of seborrheic dermatitis.…”