Sordarin -- the antifungal antibiotic with unique modus operandi

Abstract

Fungal infections cause serious problems in many aspects of human life; especially infections by fungal species represent problems in immunocompromised patients. Current antifungal antibiotics target various metabolic pathways, predominantly the cell wall or cellular membrane. However, numerous compounds are available to combat fungal infections, their efficacy is far from being satisfactory and some of them display substantial toxicity. The emerging resistance represents a serious issue as well; thus, there is a considerable need for new anti-fungal compounds with lower toxicity and higher effectiveness. One of the unique antifungal antibiotics is sordarin, the only known compound that acts on the fungal translational machinery per se. It has been shown that sordarin inhibits protein synthesis at the elongation step of the translational cycle, acting on eukaryotic elongation-factor-2. In this review, we are aiming to deliver a robust scientific platform promoting the development of antifungal compounds, especially focusing on molecular action of sordarin.

Yeast gene KTI13 (alias DPH8) operates in the initiation step of diphthamide synthesis on elongation factor 2

“…2A). As shown previously, sordarin resistance is a trait diagnostic for failure to initiate or complete EF2 modification with diphthamide [39,41]. Thus, two out of five Elongator regulators tested, apparently share dual-functional roles in tRNA and EF2 modification pathways: Kti11/Dph3 and Kti13.…”

“…2A). When we compared growth of this mutant set in the presence of sordarin, a diphthamide-dependent EF2 inhibitor other than DT [22,41], solely kti11/dph3Δ and kti13Δ cells would protect against the antifungal (Fig. 2A).…”