Antifungal echinocandins: Historical discovery, comprehensive structure-activity relationships, resistance mechanisms...

Before the 2000s, the antifungal toolbox against invasive fungal infections (IFIs) was only composed of very toxic amphotericin B, weakly selective and nearly unused 5-fluorocytosine and azoles that have been massively used in agriculture and horticulture. The emergence of resistances followed their respective launch, so many antifungals became progressively inefficient whereas the antifungal research was left behind. In the 2000s, echinocandins (ECs) were introduced as a new antifungal class of natural origin and of unprecedented mechanism of action. ECs, especially first-in-class caspofungin, are reputed to inhibit β-(1,3)-D-glucan synthase, an enzyme involved in the biosynthesis of the fungal cell wall. Their lipocyclohexapeptidic semisynthetic nature and their original mechanism of action made them reliable therapeutic agents for the treatment of fungal nosocomial infections. Advantageously, their weak hepatic metabolism and slow elimination limit drug-drug interactions in polymedicated patients or those with liver or renal dysfunctions. After a general introduction, here we report historical facts about ECs' discovery and development. The ECs' mechanism of action is then tackled under the structural angle, enlightening the importance of recent results from chemical biology and molecular modelling approaches in the knowledge of this important therapeutic class. The heart of our work is a comprehensive updated review on structure-activity (SAR) and structure-properties relationships (SPR) related to this family. Finally, resistance data are discussed and presented in tables to facilitate their consulting. We finally list the most relevant antifungal drug candidates, highlighting the importance of the chemical angle in expanding the antifungal therapeutic arsenal. As lipopeptides are amphiphilic middle-size substances and the glucan synthase a complex transmembrane target, many functional details remain to be discovered regarding ECs' modalities of action to circumvent arising resistances. In this pursuit, medicinal chemistry has a significant role to play.