drafted, reviewed and edited the manuscript. 1200 kDa [2,6], possibly resulting in their poor oral absorption [3,7,8]. Furthermore, distribution of the first-generation echinocandins to the central nervous system, intraocular fluids, and urine is poor, mainly due to their high protein-binding capabilities ( 99%) and high molecular masses [3,7,8]. Active research into new drugs by high throughput screening of natural products from endophytic fungi led to the discovery of enfumafungin, a triterpene glycoside [9]. Enfumafungin is structurally distinct from echinocandins (Figure 1) [10,11], forming a new class of antifungals called fungerps (Antifungal Triterpenoid) [12,13,14]. Modifications of enfumafungin for improved oral bioavailability and pharmacokinetic properties led to the development of the semi-synthetic derivative, which was named ibrexafungerp (IBX) [15] by the World Health Organizations international non-proprietary name group [16]. Open in a separate window Figure 1 This is a figure comparing Fungerp and Echinocandin chemical structures (modified from [10,11]). 2. Mechanism of Action and Resistance Ibrexafungerp (formerly SCY-078 or MK-3118) is a first-in-class triterpenoid antifungal that inhibits biosynthesis of -(1,3)-D-glucan in the fungal cell wall. Glucan represents 50C60% of the fungal 5-hydroxytryptophan (5-HTP) cell wall dry weight [17]. -(1,3)-D-glucan is the most important component of the fungal wall, as many structures are covalently linked to it [17]; furthermore, it is the most abundant molecule in many fungi (65C90%) [17,18], making it an important antifungal target [1,12]. Inhibition of -(1,3)-D-glucan biosynthesis compromises the fungal cell wall by making it highly permeable, disrupting osmotic pressure, which can lead to cell lysis [19,20,21]. -(1,3)-D-glucan synthase is a transmembrane glycosyltransferase enzyme complex comprised of a catalytic Fks1p subunit encoded by the homologous genes and [22] and a third gene, [23]; a rho GTPase regulatory subunit encoded by the Rgene [24]. The catalytic unit binds UDP-glucose and the regulatory subunit binds GTP to COG3 catalyse the polymerization of UDP-glucose to -(1,3)-D-glucan [25], which is incorporated into the fungal cell wall, where it 5-hydroxytryptophan (5-HTP) functions mainly to maintain the structural integrity of the cell wall 5-hydroxytryptophan (5-HTP) [19,20,21]. Ibrexafungerp (IBX) has a similar mechanism of action to the echinocandins [26,27] and acts by non-competitively inhibiting the -(1,3) D-glucan synthase enzyme [12,27]. As with echinocandins, IBX has a fungicidal effect on spp. [28] and a fungistatic effect on spp. [29,30]. However, the ibrexafungerp and echinocandin-binding sites on the enzyme are not the same, but partially overlap resulting in very limited cross-resistance between echinocandin- and ibrexafungerp-resistant strains [26,27,31]. Resistance to echinocandins is due to mutations in the genes, encoding for the catalytic site of the -(1,3) D-glucan synthase enzyme complex; specifically, mutations in two areas 5-hydroxytryptophan (5-HTP) designated as hot spots 1 and 2 [32,33], have been associated with reduced susceptibility to echinocandins [33,34]. The -(1,3) D-glucan synthase enzyme complex is critical for fungal cell wall activity; alterations of the catalytic core are associated with a decrease in the enzymatic reaction rate, causing slower -(1,3) D-glucan biosynthesis [35]. Widespread use and prolonged courses of echinocandins have led to echinocandin resistance in spp., especially and [36,37,38,39,40]. Ibrexafungerp has potent activity against echinocandin-resistant (ER) with mutations [41], although certain mutants have increased IBX MIC values, leading to 1.6C16-fold decreases in IBX susceptibility, compared to the wild-type strains [31]. Deletion mutations in the (F625del) and genes (F659del) lead to 40-fold and 121-fold increases in the MIC50 for IBX, respectively [31]. Furthermore, two additional mutations, W715L and A1390D, outside the hotspot 2 region in the gene, resulted in 29-fold and 20-fold increases in the MIC50 for IBX, respectively [31]. The majority of resistance mutations to IBX in are located in the gene [31,40], consistent with the hypothesis that biosynthesis of -(1,3) D-glucan in is mostly mediated through.