Fungi cause death of over 1.5 million people every year, while cutaneous mycoses are among the most common infections in the world. Mycoses vary greatly in severity, there are long-term skin (ringworm), nail or hair infections (tinea capitis), recurrent like vaginal candidiasis or severe, life-threatening systemic, multiorgan infections. In the last few years, increasing importance is attached to the health and economic problems caused by fungal pathogens. There is a growing need for improvement of the availability of antifungal drugs, decreasing their prices and reducing side effects. Searching for novel approaches in this respect, amino acid and protein biosynthesis pathways appear to be competitive. The route that leads from amino acid biosynthesis to protein folding and its activation is rich in enzymes that are descriptive of fungi. Blocking the action of those enzymes often leads to avirulence or growth inhibition. In this review, we want to trace the principal processes of fungi vitality. We present the data of genes encoding enzymes involved in amino acid and protein biosynthesis, potential molecular targets in antifungal chemotherapy, and describe the impact of inhibitors on fungal organisms.

Acridine cell-penetrating peptide conjugates are an extremely important family of compounds in antitumor chemotherapy. These conjugates are not so widely analysed in antimicrobial therapy, although bioactive peptides could be used as nanocarriers to smuggle antimicrobial compounds. An octaarginine conjugate of an imidazoacridinone derivative (Compound 1-R8) synthetized by us exhibited high antifungal activity against reference and fluconazole-resistant clinical strains (MICs ≤ 4 μg mL⁻¹). Our results clearly demonstrate the qualitative difference in accumulation of the mother compound and Compound 1-R8 conjugate into fungal cells. Only the latter was transported and accumulated effectively. Microscopic and flow cytometry analysis provide some evidence that the killing activity of Compound 1-R8 may be associated with a change in the permeability of the fungal cell membrane. The conjugate exhibited low cytotoxicity against human embryonic kidney (HEK-293) and human liver (HEPG2) cancer cell lines. Nevertheless, the selectivity index value of the conjugate for human pathogenic strains remained favourable and no hemolytic activity was observed. The inhibitory effect of the analysed compound on yeast topoisomerase II activity suggested its molecular target. In summary, conjugation with R8 effectively increased imidazoacridinone derivative ability to enter the fungal cell and achieve a concentration inside the cell that resulted in a high antifungal effect.

Amino adds constitute the key sources of nitrogen for growth of Candida albicans. In order to survive inside the host in different and rapidly changing environments, this fungus must be able to adapt via its expression of genes for amino acid metabolism. We analysed the ARO8, ARO9, YER152C, and BNA3 genes with regards to their role in the nutritional flexibility of C. albicans. CaAro8p is undoubtedly the most versatile enzyme among the aminotransferases investigated. It is involved in the catabolism of histidine, lysine, and aromatic amino acids as well as in L-Lys, Phe and Tyr biosynthesis. CaAro9p participates in the catabolism of aromatic amino acids and lysine at high concentrations of these compounds, with no biosynthetic role. Conversely, the CaYer152Cp catalytic potential for aromatic amino acid catabolism observed in vitro appears to be of little importance in vivo. Neither biosynthetic nor catabolic roles of CaBan3p were observed for any proteinogenic amino acid. Finally, none of the analysed aminotransferases was solely responsible for the catabolism of a single particular amino acid or its biosynthesis.

Fungal pathogens are considered as serious factors for deadly diseases and are a case of medical concern. Invasive fungal infections also complicate the clinical course of COVID-19, leading to a significant increase in mortality. Furthermore, fungal strains' multidrug resistance has increased the demand for antifungals with a different mechanism of action. The present study aimed to identify antifungal compounds targeting yeast topoisomerase II (yTOPOII) derived from well-known human topoisomerase II (hTOPOII) poisons C-1305 and C-1311. Two sets of derivatives: triazoloacridinones (IKE1-8) and imidazoacridinones (IKE9-14) were synthetized and evaluated with a specific emphasis on the molecular mechanism of action. Our results indicated that their effectiveness as enzyme inhibitors was not solely due to intercalation ability but also as a result of influence on catalytic activity by the formation of covalent complexes between plasmid DNA and yTOPOII. Lysine conjunction increased the strength of the compound's interaction with DNA and improved penetration into the fungal cells. Triazoloacridinone derivatives in contrast to starting compound C-1305 exhibited moderate antifungal activity and at least twice lower cytotoxicity. Importantly, compounds (IKE5-8) were not substrates for multidrug ABC transporters whereas a derivative conjugated with lysine (IKE7), showed the ability to overcome C. glabrata fluconazole-resistance (MIC 32–64 µg mL⁻¹).

In the last few years, increasing importance is attached to problems caused by fungal pathogens. Current methods of preventing fungal infections remain unsatisfactory. There are several antifungal compounds which are highly effective in some cases, however, they have limitations in usage: Nephrotoxicity and other adverse effects. In addition, the frequent use of available fungistatic drugs promotes drug resistance. Therefore, there is an urgent need for the development of a novel antifungal drug with a different mechanism of action, blocking of the fungal DNA topoisomerases activity appear to be a promising idea. According to previous studies on the m-AMSA moderate inhibitory effect on fungal topoisomerase II, we have decided to study Capridine β (also acridine derivative) antifungal activity, as well as its inhibitory potential on yeast topoisomerase II (yTOPOII). Results indicated that Capridine β antifungal activity depends on the kind of strains analyzed (MICs range 0.5–64 μg mL⁻¹) and is related to its biotransformation in the cells. An investigation of metabolite formation, identified as Capridine β reduction product (IE1) by the fungus Candida albicans was performed. IE1 exhibited no activity against fungal cells due to an inability to enter the cells. Although no antifungal activity was observed, in contrast to Capridine β, biotransformation metabolite totally inhibited the yTOPOII-mediated relaxation at concentrations lower than detected for m-AMSA. The closely related Capridine β only slightly diminished the catalytic activity of yTOPOII.

L-methionine (L-Met) is one of the nine proteinogenic amino acids essential for humans since, in human cells, there are no complete pathways for its biosynthesis from simple precursors. L-Met plays a crucial role in cellular function as it is required for proper protein synthesis, acting as an initiator. Additionally, this amino acid participates in various metabolic processes and serves as a precursor for the synthesis of S-adenosylmethionine (AdoMet), which is involved in the methylation of DNA molecules and phospholipids, as well as in maintaining genome stability. Due to its importance, fungal L-methionine biosynthesis pathway enzymes are being intensively studied. This review presents the current state of the art in terms of their cellular function, usefulness as molecular markers, antifungal targets, or industrial approaches.