Fungal Biofilms as a Valuable Target for the Discovery of Natural Products That Cope with the Resistance of Medically Important Fungi-Latest Findings

Abstract

The development of new antifungal agents that target biofilms is an urgent need. Natural products, mainly from the plant kingdom, represent an invaluable source of these entities. The present review provides an update (2017-May 2021) on the available information on essential oils, propolis, extracts from plants, algae, lichens and microorganisms, compounds from different natural sources and nanosystems containing natural products with the capacity to in vitro or in vivo modulate fungal biofilms. The search yielded 42 articles; seven involved essential oils, two Brazilian propolis, six plant extracts and one of each, extracts from lichens and algae/cyanobacteria. Twenty articles deal with the antibiofilm effect of pure natural compounds, with 10 of them including studies of the mechanism of action and five dealing with natural compounds included in nanosystems. Thirty-seven manuscripts evaluated Candida spp. biofilms and two tested Fusarium and Cryptococcus spp. Only one manuscript involved Aspergillus fumigatus. From the data presented here, it is clear that the search of natural products with activity against fungal biofilms has been a highly active area of research in recent years. However, it also reveals the necessity of deepening the studies by (i) evaluating the effect of natural products on biofilms formed by the newly emerged and worrisome health-care associated fungi, C. auris, as well as on other non-albicans Candida spp., Cryptococcus sp. and filamentous fungi; (ii) elucidating the mechanisms of action of the most active natural products; (iii) increasing the in vivo testing.

Keywords: Candida spp.; Cryptococcus spp.; Fusarium spp.; antifungal resistance; filamentous fungi; fungal biofilm; mechanisms of antibiofilm action; natural products.

Figure 1

(a) The five-stage process involved in the development of biofilm: 1. adherence of yeasts to a surface followed by yeast-to-hyphal transition; 2. the exopolymeric matrix (EPM) is produced resulting in a firmly adhered “irreversible” attachment; 3. early biofilm architecture is developed; 4. the biofilm reaches maturation in a three-dimensional structure and 5. single planktonic cells are dispersed from the mature biofilm. Reproduced from Stoodley et al., 2002 [49]. Image credit: D. Davies, with permission of Prof. David Davies. (b) A clearer scheme of stage 1. Yeasts adhere to host cell surfaces. Contact to host cells triggers the yeast-to-hyphal transition and directed growth via thigmotropism. Reproduced from part of Figure 1a from Mayer et al. [51], with permission. (c) A scan electron microscopy (SEM) image of a mature (48 h) Candida albicans biofilm (formed in stage 4 of Figure 1a). Bar = 10 µm. Yeasts, hyphae, and pseudohyphae can be observed. Most EPM was lost during the SEM procedures. Reproduced from Ramage et al. [50] with permission.