Table 2.
Novel antifungals: target, mechanism of action, spectrum, advantages and stage of development.
| Antifungal drug class | Antifungal drug name | Cell target Mechanism of action | Spectrum in resistant Candida spp | Clinical advantages | Stage of development |
|---|---|---|---|---|---|
| Tetrazole | VT1129 VT1161 VT1598 |
Cell membrane Inhibition of Erg11/Cyp51 Inhibition of ergosterol biosynthesis |
C. albicans
C. glabrata C. auris C. krusei |
More specific fungal Cyp51 inhibitor; fewer drug interactions; oral | Pre-clinical for IC (Phase I cryptococcal meningitis) Phase III VVC FDA QIDP Phase I |
| Echinocandin | Rezafungin | Cell wall Inhibition of β-1,3-glucan synthase |
C. albicans
C. glabrata C. krusei C. auris |
Superior PK/PD – intermittent dosing penetration (including gut) | Phase III IC and prophylaxis BMT FDA QIDP and fast track aproval |
| Polyene | MAT2203 (encochleated Amphotericin B) | Organelle membranes Sequesters ergosterol out of cell membrane |
C. albicans
C. glabrata C. krusei C. lusitaniae |
Oral; less toxic than IV fromulation | Phase II VVC and CMC FDA QIDP |
| Triterpenoids | Ibrexafungerp | Cell wall Inhibition of β-1,3-glucan synthase |
C. albicans
C. glabrata C. auris |
Oral; well tolerated; penetrates gut abscesses; separate binding site |
Phase III IC, VVC and CMC; C auris |
| N-phosphonooxymethylene | Fosmanogepix | Cell wall Inhibits GPI anchored biosynthesis |
C. albicans
C. glabrata C. auris C. parapsilosis |
Novel mechanism of action; Oral; Extensive tissue distribution; Limited cross-resistance |
Phase II open label IC/C auris
FDA fast track approval |
| Arylamidines | ATI-2307 (formerly T2307) | Mitochondria Collapses mitochondrial membrane potential |
C. albicans
C. glabrata C. krusei C. auris |
Novel mechanism of action; Active against biofilms |
Phase I |
| Hydrazycins | BHBM D0, D13 |
Cell cycle Inhibit vesicular trafficking of sphingolipid precursors |
C. glabrata
C. krusei |
Novel target | Pre-clinical |
| Trehalose inhibitors | Tps1 and Tps2 inhibitors | Fungal virulence Inhibition of glycolysis |
Compound discovery | ||
| Acetyl CoA synthetase inhibitors | AR-12 | Disruption of carbon metabolism, histone acetylation, ribosome function, autophagy |
C. albicans
C. glabrata C. krusei |
Novel mechanism of action; Active against resistant species; Well tolerated |
Phase I (cancer) |
| Calcium/calcineurin inhibitors | Cyclosporin A and Tacrolimus (FK506) | Stress response inhibitor Inhibition of calcineurin |
C. albicans
C. glabrata C. krusei |
Inhibit stress-response pathways; fungicidal in combination with current antifungals; abrogate tolerance; non immunosuppressive derivatives developed | Pre-clinical |
| Hsp90 inhibitors | Efungumab and geldanamycin | Stress response inhibitor Hsp90 inhibitor |
C. albicans | Inhibit stress response pathways; fungicidal in combination with current antifungals; abrogate tolerance | Phase III IC (enfungumab): not granted EMA approval |
| Histone deacetylase inhibitors | MGCD290 | Nucleus Inhibition of Hos2 and Hsp90 |
C. albicans
C. glabrata C. krusei |
Combination with current antifungals; Abrogate tolerance |
Phase II VVC |
| Antibiotics | Colistin | Cell membrane Enhanced ergosterol depletion |
C. albicans | Combination with current antifungals; abrogate tolerance | Pre-clinical |
VVC, vulvovaginal candidiasis; IC, invasive candidiasis; BMT, bone marrow transplant; CMC, chronic mucocutaneous candidiasis; FDA, Federal Drug Administration (USA); QIDP, qualified infectious diseases product; EMA, European Medicine Agency.