TABLE 2.
New and emerging antifungal agents for eumycetoma: pre-clinical data.
| Class of drug | In vitro susceptibility | In vivo efficacy (M. mycetomatis) | Comments | |
|---|---|---|---|---|
| M. mycetomatis, MIC50 or range (ug/mL unless stated otherwise) | Pleosporalean fungi*, IC range | |||
| Triazoles | ||||
| Mechanism of action: inhibition of lanosterol demethylase in the ergosterol biosynthesis pathway | ||||
| Itraconazole | 0.03 | 0.125–8 | No - not in invertebrate model or mouse model | |
| Posaconazole | <0.03 | 0.03–1 | Yes - improved survival in invertebrate model (dose-dependent) | |
| Voriconazole | 0.06 | 0.125–1 | No - not in invertebrate model | |
| Isavuconazole | 0.03 | NA | NA | |
| Ravuconazole | 0.008 | 0.008–8 | Yes - improved survival in invertebrate model | Fosravuconazole in clinical trial |
| Bitertanol | 0.06 uM | NA | Yes - improved survival in invertebrate model | In use as a pesticide |
| Difenoconazole | 0.06 uM | NA | Yes - reduced number and size of grains | In use as a pesticide |
| Imidazoles | ||||
| Mechanism of action: inhibition of lanosterol demethylase in the ergosterol biosynthesis pathway | ||||
| Ketoconazole | 0.125 | NA | No - not in invertebrate model | |
| Luliconazole | 0.001 | 0.004–0.064 | NA | Only available in topical formulation |
| Lanoconazole | 0.002 | 0.008–0.125 | NA | Only available in topical formulation |
| Tetrazoles | ||||
| Mechanism of action: inhibition of lanosterol demethylase in the ergosterol biosynthesis pathway | ||||
| Oteseconazole | 1 uM | NA | No - not in invertebrate model | |
| Allylamines | ||||
| Mechanism of action: inhibition of squalene epoxidase in the ergosterol biosynthesis pathway | ||||
| Terbinafine | 8 | NA | Yes - improved survival in invertebrate model | |
| Echinocandins | ||||
| Mechanism of action: inhibition of 1,3-beta-D-glucan synthase in the cell wall biosynthesis pathway | ||||
| Caspofungin | 64 | 8 - >16 | NA | |
| Anidulafungin | 128 | NA | NA | |
| Micafungin | 128 | NA | NA | |
| Orotomides | ||||
| Mechanism of action: inhibition of dihydroorotate dehydrogenase in the de novo pyrimidine biosynthesis pathway | ||||
| Olorofim | 0.016 | NA | Yes - improved survival in invertebrate model | |
| Polyenes | ||||
| Mechanism of action: binds directly to ergosterol in the cell membrane | ||||
| Amphotericin B | 0.5 | 0.125–16 | Yes - improved survival in invertebrate model, prevented grain formation in mouse model | |
| Fenarimol analogues | ||||
| Mechanism of action: putative inhibition of lanosterol demethylase in the ergosterol biosynthesis pathway | ||||
| EPL-BS1246 | 1 | NA | Yes - reduced number and size of grains | |
| EPL-BS0178 | 8 | NA | Yes - improved survival in invertebrate model | |
| EPL-BS0495 | 4 | NA | Yes - improved survival in invertebrate model | |
| EPL-BS1025 | 4 | NA | Yes - improved survival in invertebrate model | |
| Salicylanilides | ||||
| Mechanism of action: induces mitochondria-to-nucleus retrograde response | ||||
| Niclosamide | 0.78–1.6 | NA | NA | |
| Niclosamide-ethanolamine | 0.78–1.6 | NA | NA | |
| MMV665807 | 1.6 | NA | NA | |
| Benzimidazole carbamates | ||||
| Mechanism of action: binds to β-tubulin and destabilises microtubule formation | ||||
| Fenbendazole | 0.5 | Inhibits growth | Yes - improved survival in invertebrate model | |
| Carbendazim | 0.5 | Inhibits growth | Yes - partially improved survival in invertebrate model | |
| MMV1782387 | 4 | Inhibits growth | Yes - improved survival in invertebrate model | |
| 8-Aminoquinolines | ||||
| Mechanism of action: unknown | ||||
| Tafenoquine | 4 | Inhibits growth | No - not in invertebrate model | |
| Strobilurins | ||||
| Mechanism of action: binds to cytochrome b to inhibit mitochondrial respiration | ||||
| Azoxystrobin | 0.06 | NA | Yes - reduced number and size of grains | In use as a pesticide |
| Trifloxystrobin | 0.25 | NA | Yes - reduced number and size of grains | In use as a pesticide |
| Aminothiazole derivatives | ||||
| Mechanism of action: inhibition of calcium-activated small conductance potassium channels | ||||
| MMV006357 | 0.25 | NA | Yes - improved survival in invertebrate model | |
| Folate inhibitors | ||||
| Mechanism of action: dihydrofolate reductase (DHFR) inhibition | ||||
| MMV675968 | 2 | NA | Yes - partially improved survival in invertebrate model | |
| Pyrazolopyrimidines | ||||
| Mechanism of action: unknown | ||||
| MMV022478 | 4 | NA | Yes - partially improved survival in invertebrate model | |
| Quinoline derivatives | ||||
| Mechanism of action: unknown | ||||
| Iodoquinol | 8 | NA | NA | |
| Plant extracts and essential oils | ||||
| Mechanism of action: unknown | ||||
| CIN-102 | 128 | NA | Yes - improved survival in invertebrate model | |
| Other | ||||
| Mechanism of action: unknown | ||||
| MMV1578570 | Inhibits growth | Inhibits growth | NA | |
*includes Falciformispora senegalensis, Trematosphaeria grisea, Nigrograna mackinnonii and Medicopsis romeroi.
NA—data not available