Rezafungin—Mechanisms of Action, Susceptibility and Resistance: Similarities and Differences with the Other Echinocandins

Abstract

Rezafungin (formerly CD101) is a new β-glucan synthase inhibitor that is chemically related with anidulafungin. It is considered the first molecule of the new generation of long-acting echinocandins. It has several advantages over the already approved by the Food and Drug Administration (FDA) echinocandins as it has better tissue penetration, better pharmacokinetic/phamacodynamic (PK/PD) pharmacometrics, and a good safety profile. It is much more stable in solution than the older echinocandins, making it more flexible in terms of dosing, storage, and manufacturing. These properties would allow rezafungin to be administered once-weekly (intravenous) and to be potentially administered topically and subcutaneously. In addition, higher dose regimens were tested with no evidence of toxic effect. This will eventually prevent (or reduce) the selection of resistant strains. Rezafungin also has several similarities with older echinocandins as they share the same in vitro behavior (very similar Minimum Inhibitory Concentration required to inhibit the growth of 50% of the isolates (MIC50) and half enzyme maximal inhibitory concentration 50% (IC50)) and spectrum, the same target, and the same mechanisms of resistance. The selection of FKS mutants occurred at similar frequency for rezafungin than for anidulafungin and caspofungin. In this review, rezafungin mechanism of action, target, mechanism of resistance, and in vitro data are described in a comparative manner with the already approved echinocandins.

Molecular Mechanisms of Resistance to Antifungals in Candida albicans

“…The main issues faced by the development of new drugs are: 1) they must have a broad spectrum against emerging filamentous yeasts and fungi and 2) they must have a more efficient fungicidal activity to eliminate pathogens quickly and totally [55][56][57][58][59]. Besides, invasive candidiasis occurs in very frail patients who do not tolerate much organ toxicity, since such patients are often taking many other therapeutic agents, so drug-drug interactions must be carefully considered [60].…”

“…Several new chemical-antifungals are designed specifically to target either 1,3-β-d-glucan (such as Rezafungin and Ibrexafungerp) or ergosterol (such as the compound VT-1161). These compounds are very specific for fungal infections or they have a longer half-life, offering better efficacy [58,[60][61][62]. At the same time, several of these antifungal agents have new targets and subsequently, new mechanisms of action.…”

One Century of Study: What We Learned about Paracoccidioides and How This Pathogen Contributed to Advances in Antifungal Therapy

“…Thus, echinocandins showed no promising antifungal activity in the in vitro assays against Paracoccidioides sp., especially against yeast [ 81 , 82 ]. In addition, the most recent inhibitors Ibrexafungerp [ 83 ] and rezafungin [ 84 ] have not yet been evaluated for in vitro or in vivo activity in the PCM model.…”

Special Issue: Antifungal Agents Recently Approved or under Development

“…As with the established echinocandins, rezafungin MICs are low including resistant/mutant Candida , C. auris and Aspergillus isolates and the presence of FKS mutants at a similar frequency [ 2 ]. It has no activity against the Mucorales, Fusarium spp.…”

“…It has no activity against the Mucorales, Fusarium spp. and Ajellomycetaceae ; it also shows the lowest frequency of paradoxical effect and trailing [ 2 , 3 ]. It has better tissue penetration, prolonged pharmacokinetics/phamacodynamic (PK/PD), pharmacometrics, and a better safety profile than established echinocandins.…”