Strategies against antifungal resistance

A recent paper in Drug Design, Development and Therapy gives an overview on the new strategies to combat antifungal drug resistance [1].

Antifungal resistance is increasing and that poses a growing threat to the people with fungal infections, especially to the immunocompromised patients. The most commonly used antifungal agents are triazoles, echinocardins and polyenes. The main strategies against antifungal drug resistance include targeting

• heat shock proteins (Hsp90, Hsp21, Hsp70). Inhibition of Hsp90 not only decreases azole resistance but also reduces biofilm formation. A biofilm is a structured fungal community attached to the surface of an object (intravascular catheters, implants, etc.) surrounded by an extracellular matrix shielding pathogenic fungi against antifungals.
• calcineurin crucial to growth, virulence, drug resistance, stress response and transition between morphological states for a broad spectrum of fungi. Combining a calcineurin inhibitor with other antifungals (e.g. cyclosporin A, tacrolimus, caspofungin, shows synergistic effect.
• trehalose biosynthesis. Trehalose, also referred to as α-D-glucopyranosyl-(1,1)-α-D-glucopyranoside, is a simple nonreducing disaccharide containing two glucose subunits connected by an α,α-1,1-glycosidic linkage. Inhibition of the enzymes involved in trehalose biosynthesis e.g. with validamycin A is a possibility.
• sphingolipids, important ingredients of fungal membrane. There are several drugs inhibiting sphingolipid-metabolizing enzymes (myriocin, sphingofungin, australofungin, fumonisin B1, rustmicin) and inhibiting sphingolipid function (defensin).

It is also interesting for a cyclodextrin researcher that several studies proved the antifungal effect of a polysaccharide, chitosan (N-deacetylated chitin): it inhibits hyphal growth, pore germination, biofilm formation. Especially strong anti-biofilm formation effect was demonstrated by carboxymethyl chitosan.

The paper does not mention that the antifungal resistance might be influenced by formulation e.g. by cyclodextrins. Both triazoles and polyenes can be formulated with cyclodextrins. The itraconazole/HPBCD (Janssen), posaconazole/SBEBCD (Merck), voriconazole/SBEBCD (Pfizer) and voriconazole/HPBCD (Rambaxy, TEVA) formulations have been marketed. The advantages of complexation of polyene antifungal agents such as amphotericin B (AmB) and nystatin have been thoroughly studied. For instance, the AmB-γ-CD complex showed significantly higher inhibition activity on biofilm formation, efficient penetration through yeast biofilms and higher fungicidal activity on biofilm cells compared to AmB dissolved in DMSO [2]. γ-CD has shown a synergistic effect on membrane destabilization with AmB.

1. Zheng, Y.H., Ma, Y.Y., Ding, Y., Chen, X.Q., Gao, G.X. An insight into new strategies to combat antifungal drug resistance. Drug Design, Development and Therapy 2018:12 3807–3816. https://doi.org/10.2147/DDDT.S185833
2. Ruiz, H.K., Serrano, D.R., Dea-Ayuela, M.A., Bilbao-Ramos, P.E., Bolas-Fernandez, F., Torrado, J.J., Molero, G. New amphotericin B-gamma cyclodextrin formulation for topical use with synergistic activity against diverse fungal species and Leishmania spp. International Journal of Pharmaceutics 2014, 473(1-2), pp. 148-157.
   https://doi.org/10.1016/j.ijpharm.2014.07.004

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