Modes of action of the new arylguanidine abafungin beyond interference with ergosterol biosynthesis and in vitro activity against medically important fungi

Abstract

Background: In contrast to the increasing numbers of agents for the treatment of invasive fungal infections, discoveries of new antifungal agents with therapeutic value in dermatomycoses are reported only rarely.

Methods: Abafungin (chemical abstracts service registry No. 129639-79/8) is the first member of a novel class of synthetic antifungal compounds, the arylguanidines. It was first synthesized at Bayer AG, Leverkusen, Germany, and its antifungal action was discovered during the screening of H(2)-receptor antagonists based on the structure of famotidine. To obtain insight into its mode of action and antifungal activity, various tests were carried out with different fungal pathogens in vitro.

Results: Abafungin was found to have potent antifungal activity. Furthermore, mode-of-action studies suggested that abafungin exerts its antifungal activity regardless of whether the pathogens are growing or in a resting state. One target of abafungin was found to be the inhibition of transmethylation at the C-24 position of the sterol side chain, catalyzed by the enzyme sterol-C-24-methyltransferase. A second action of abafungin seems to be a direct effect on the fungal cell membrane.

Conclusion: The observed characteristics of abafungin indicate that abafungin might be a promising antifungal agent defining a new class of antimycotics.

Fig. 1.

Chemical structure of famotidine (a) and abafungin (b).

Fig. 2.

Fungicidal activity of different antifungals against 39 clinical isolates of dermatophytes in demineralized water.

Fig. 3.

Fungicidal activity of different antifungals against 39 clinical isolates of yeasts in physiological saline. MFC (99% reduction of 10⁴ CFU/ml) was determined after 3 days of incubation at 37°C.

Fig. 4.

Increase in conductivity by abafun-gin. Inoculum size of C. albicans H12: 10⁸ CFU/ml in distilled water.

Fig. 5.

Effect of abafungin on the release of potassium from C. albicans TIMM0144.

Fig. 6.

ATP leakage and degradation of C. albicans H12 induced by abafungin in bidistilled water.

Fig. 7.

ATP in growing cells of C. albicans H12 treated with abafungin in YMM (pH 5.0).

Fig. 8.

Difference spectra of abafungin with phospholipids. In each case, the baseline (bl) and the difference spectrum from 190 nm (left side) to 350 nm is shown. The concentrations of all phospholipids and of abafungin were 10⁻⁴ M, except for phosphatidylserine + abafungin (each 5 × 10⁻⁵M).

Fig. 9.

Dual mode of action of abafungin by inhibition of the ergosterol biosynthesis and direct impairment of the cell membrane. SAM = S-adenosyl-L-methionine; SMT =sterol-C-24 methyltransferase.