The epidemiology of invasive fungal infections is changing, with new populations at risk and the emergence of resistance caused by the selective pressure from increased usage of antifungal agents in prophylaxis, empiric therapy, and agriculture. Limited antifungal therapeutic options are further challenged by drug–drug interactions, toxicity, and constraints in administration routes. Despite the need for more antifungal drug options, no new classes of antifungal drugs have become available over the last 2 decades, and only one single new agent from a known antifungal class has been approved in the last decade. Nevertheless, there is hope on the horizon, with a number of new antifungal classes in late-stage clinical development. In this review, we describe the mechanisms of drug resistance employed by fungi and extensively discuss the most promising drugs in development, including fosmanogepix (a novel Gwt1 enzyme inhibitor), ibrexafungerp (a first-in-class triterpenoid), olorofim (a novel dihyroorotate dehydrogenase enzyme inhibitor), opelconazole (a novel triazole optimized for inhalation), and rezafungin (an echinocandin designed to be dosed once weekly). We focus on the mechanism of action and pharmacokinetics, as well as the spectrum of activity and stages of clinical development. We also highlight the potential future role of these drugs and unmet needs.

Novel species of fungi described in this study include those from various countries as follows: Australia: Apiognomonia lasiopetali on Lasiopetalum sp., Blastacervulus eucalyptorum on Eucalyptus adesmophloia, Bullanockia australis (incl. Bullanockia gen. nov.) on Kingia australis, Caliciopsis eucalypti on Eucalyptus marginata, Celerioriella petrophiles on Petrophile teretifolia, Coleophoma xanthosiae on Xanthosia rotundifolia, Coniothyrium hakeae on Hakea sp., Diatrypella banksiae on Banksia formosa, Disculoides corymbiae on Corymbia calophylla, Elsinoë eelemani on Melaleuca alternifolia, Elsinoë eucalyptigena on Eucalyptus kingsmillii, Elsinoë preissianae on Eucalyptus preissiana, Eucasphaeria rustici on Eucalyptus creta, Hyweljonesia queenslandica (incl. Hyweljonesia gen. nov.) on the cocoon of an unidentified microlepidoptera, Mycodiella eucalypti (incl. Mycodiella gen. nov.) on Eucalyptus diversicolor, Myrtapenidiella sporadicae on Eucalyptus sporadica, Neocrinula xanthorrhoeae (incl. Neocrinula gen. nov.) on Xanthorrhoea sp., Ophiocordyceps nooreniae on dead ant, Phaeosphaeriopsis agavacearum on Agave sp., Phlogicylindrium mokarei on Eucalyptus sp., Phyllosticta acaciigena on Acacia suaveolens, Pleurophoma acaciae on Acacia glaucoptera, Pyrenochaeta hakeae on Hakea sp., Readeriella lehmannii on Eucalyptus lehmannii, Saccharata banksiae on Banksia grandis, Saccharata daviesiae on Daviesia pachyphylla, Saccharata eucalyptorum on Eucalyptus bigalerita, Saccharata hakeae on Hakea baxteri, Saccharata hakeicola on Hakea victoria, Saccharata lambertiae on Lambertia ericifolia, Saccharata petrophiles on Petrophile sp., Saccharata petrophilicola on Petrophile fastigiata, Sphaerellopsis hakeae on Hakea sp., and Teichospora kingiae on Kingia australis. Brazil: Adautomilanezia caesalpiniae (incl. Adautomilanezia gen. nov.) on Caesalpina echinata, Arthrophiala arthrospora (incl. Arthrophiala gen. nov.) on Sagittaria montevidensis, Diaporthe caatingaensis (endophyte from Tacinga inamoena), Geastrum ishikawae on sandy soil, Geastrum pusillipilosum on soil, Gymnopus pygmaeus on dead leaves and sticks, Inonotus hymenonitens on decayed angiosperm trunk, Pyricularia urashimae on Urochloa brizantha, and Synnemellisia aurantia on Passiflora edulis. Chile: Tubulicrinis australis on Lophosoria quadripinnata. France: Cercophora squamulosa from submerged wood, and Scedosporium cereisporum from fluids of a wastewater treatment plant. Hawaii: Beltraniella acaciae, Dactylaria acaciae, Rhexodenticula acaciae, Rubikia evansii and Torula acaciae (all on Acacia koa). India: Lepidoderma echinosporum on dead semi-woody stems, and Rhodocybe rubrobrunnea from soil. Iran: Talaromyces kabodanensis from hypersaline soil. La Réunion: Neocordana musarum from leaves of Musa sp. Malaysia: Anungitea eucalyptigena on Eucalyptus grandis × pellita, Camptomeriphila leucaenae (incl. Camptomeriphila gen. nov.) on Leucaena leucocephala, Castanediella communis on Eucalyptus pellita, Eucalyptostroma eucalypti (incl. Eucalyptostroma gen. nov.) on Eucalyptus pellita, Melanconiella syzygii on Syzygium sp., Mycophilomyces periconiae (incl. Mycophilomyces gen. nov.) as hyperparasite on Periconia on leaves of Albizia falcataria, Synnemadiella eucalypti (incl. Synnemadiella gen. nov.) on Eucalyptus pellita, and Teichospora nephelii on Nephelium lappaceum. Mexico: Aspergillus bicephalus from soil. New Zealand: Aplosporella sophorae on Sophora microphylla, Libertasomyces platani on Platanus sp., Neothyronectria sophorae (incl. Neothyronectria gen. nov.) on Sophora microphylla, Parastagonospora phoenicicola on Phoenix canariensis, Phaeoacremonium pseudopanacis on Pseudopanax crassifolius, Phlyctema phoenicis on Phoenix canariensis, and Pseudoascochyta novae-zelandiae on Cordyline australis. Panama: Chalara panamensis from needle litter of Pinus cf. caribaea. South Africa: Exophiala eucalypti on leaves of Eucalyptus sp., Fantasmomyces hyalinus (incl. Fantasmomyces gen. nov.) on Acacia exuvialis, Paracladophialophora carceris (incl. Paracladophialophora gen. nov.) on Aloe sp., and Umthunziomyces hagahagensis (incl. Umthunziomyces gen. nov.) on Mimusops caffra. Spain: Clavaria griseobrunnea on bare ground in Pteridium aquilinum field, Cyathus ibericus on small fallen branches of Pinus halepensis, Gyroporus pseudolacteus in humus of Pinus pinaster, and Pseudoascochyta pratensis (incl. Pseudoascochytagen. nov.) fromsoil. Thailand: Neoascochyta adenii on Adenium obesum, and Ochroconis capsici on Capsicum annuum. UK: Fusicolla melogrammae from dead stromata of Melogramma campylosporum on bark of Carpinus betulus. Uruguay: Myrmecridium pulvericola from house dust. USA: Neoscolecobasidium agapanthi (incl. Neoscolecobasidium gen. nov.) on Agapanthus sp., Polyscytalum purgamentum on leaf litter, Pseudopithomyces diversisporus from human toenail, Saksenaea trapezispora from knee wound of a soldier, and Sirococcus quercus from Quercus sp. Morphological and culture characteristics along with DNA barcodes are provided.

Antifungal resistance represents a major clinical challenge to clinicians responsible for treating invasive fungal infections due to the limited arsenal of systemically available antifungal agents. In addition current drugs may be limited by drug–drug interactions and serious adverse effects/toxicities that prevent their prolonged use or dosage escalation. Fluconazole resistance is of particular concern in non-Candida albicans species due to the increased incidence of infections caused by these species in different geographic locations worldwide and the elevated prevalence of resistance to this commonly used azole in many institutions. C. glabrata resistance to the echinocandins has also been documented to be rising in several US institutions, and a higher percentage of these isolates may also be azole resistant. Azole resistance in Aspergillus fumigatus due to clinical and environmental exposure to this class of agents has also been found worldwide, and these isolates can cause invasive infections with high mortality rates. In addition, several species of Aspergillus, and other molds, including Scedosporium and Fusarium species, have reduced susceptibility or pan-resistance to clinically available antifungals. Various investigational antifungals are currently in preclinical or clinical development, including several of them that have the potential to overcome resistance observed against the azoles and the echinocandins. These include agents that also target ergosterol and β-glucan biosynthesis, as well as compounds with novel mechanisms of action that may also overcome the limitations of currently available antifungal classes, including both resistance and adverse effects/toxicity.

Novel species of fungi described in the present study include the following from Australia: Vermiculariopsiella eucalypti, Mulderomyces natalis (incl. Mulderomyces gen. nov.), Fusicladium paraamoenum, Neotrimmatostroma paraexcentricum, and Pseudophloeospora eucalyptorum on leaves of Eucalyptus spp., Anungitea grevilleae (on leaves of Grevillea sp.), Pyrenochaeta acaciae (on leaves of Acacia sp.), and Brunneocarpos banksiae (incl. Brunneocarpos gen. nov.) on cones of Banksia attenuata. Novel foliicolous taxa from South Africa include Neosulcatispora strelitziae (on Strelitzia nicolai), Colletotrichum ledebouriae (on Ledebouria floridunda), Cylindrosympodioides brabejum (incl. Cylindrosympodioides gen. nov.) on Brabejum stellatifolium, Sclerostagonospora ericae (on Erica sp.), Setophoma cyperi (on Cyperus sphaerocephala), and Phaeosphaeria breonadiae (on Breonadia microcephala). Novelties described from Robben Island (South Africa) include Wojnowiciella cissampeli and Diaporthe cissampeli (both on Cissampelos capensis), Phaeotheca salicorniae (on Salicornia meyeriana), Paracylindrocarpon aloicola (incl. Paracylindrocarpon gen. nov.) on Aloe sp., and Libertasomyces myopori (incl. Libertasomyces gen. nov.) on Myoporum serratum. Several novelties are recorded from La Réunion (France), namely Phaeosphaeriopsis agapanthi (on Agapanthus sp.), Roussoella solani (on Solanum mauritianum), Vermiculariopsiella acaciae (on Acacia heterophylla), Dothiorella acacicola (on Acacia mearnsii), Chalara clidemiae (on Clidemia hirta), Cytospora tibouchinae (on Tibouchina semidecandra), Diaporthe ocoteae (on Ocotea obtusata), Castanediella eucalypticola, Phaeophleospora eucalypticola and Fusicladium eucalypticola (on Eucalyptus robusta), Lareunionomyces syzygii (incl. Lareunionomyces gen. nov.) and Parawiesneriomyces syzygii (incl. Parawiesneriomyces gen. nov.) on leaves of Syzygium jambos. Novel taxa from the USA include Meristemomyces arctostaphylos (on Arctostaphylos patula), Ochroconis dracaenae (on Dracaena reflexa), Rasamsonia columbiensis (air of a hotel conference room), Paecilomyces tabacinus (on Nicotiana tabacum), Toxicocladosporium hominis (from human broncoalveolar lavage fluid), Nothophoma macrospora (from respiratory secretion of a patient with pneumonia), and Penidiellopsis radicularis (incl. Penidiellopsis gen. nov.) from a human nail. Novel taxa described from Malaysia include Prosopidicola albizziae (on Albizzia falcataria), Proxipyricularia asari (on Asarum sp.), Diaporthe passifloricola (on Passiflora foetida), Paramycoleptodiscus albizziae (incl. Paramycoleptodiscus gen. nov.) on Albizzia falcataria, and Malaysiasca phaii (incl. Malaysiasca gen. nov.) on Phaius reflexipetalus. Two species are newly described from human patients in the Czech Republic, namely Microascus longicollis (from toenails of patient with suspected onychomycosis), and Chrysosporium echinulatum (from sole skin of patient). Furthermore, Alternaria quercicola is described on leaves of Quercus brantii (Iran), Stemphylium beticola on leaves of Beta vulgaris (The Netherlands), Scleroderma capeverdeanum on soil (Cape Verde Islands), Scleroderma dunensis on soil, and Blastobotrys meliponae from bee honey (Brazil), Ganoderma mbrekobenum on angiosperms (Ghana), Geoglossum raitviirii and Entoloma kruticianum on soil (Russia), Priceomyces vitoshaensis on Pterostichus melas (Carabidae) (Bulgaria) is the only one for which the family is listed, Ganoderma ecuadoriense on decaying wood (Ecuador), Thyrostroma cornicola on Cornus officinalis (Korea), Cercophora vinosa on decorticated branch of Salix sp. (France), Coprinus pinetorum, Coprinus littoralis and Xerocomellus poederi on soil (Spain). Two new genera from Colombia include Helminthosporiella and Uwemyces on leaves of Elaeis oleifera. Two species are described from India, namely Russula intervenosa (ectomycorrhizal with Shorea robusta), and Crinipellis odorata (on bark of Mytragyna parviflora). Novelties from Thailand include Cyphellophora gamsii (on leaf litter), Pisolithus aureosericeus and Corynascus citrinus (on soil). Two species are newly described from Citrus in Italy, namely Dendryphiella paravinosa on Citrus sinensis, and Ramularia citricola on Citrus floridana. Morphological and culture characteristics along with ITS nrDNA barcodes are provided for all taxa.

Novel species of fungi described in the present study include the following from Malaysia: Castanediella eucalypti from Eucalyptus pellita, Codinaea acacia from Acacia mangium, Emarcea eucalyptigena from Eucalyptus brassiana, Myrtapenidiella eucalyptorum from Eucalyptus pellita, Pilidiella eucalyptigena from Eucalyptus brassiana and Strelitziana malaysiana from Acacia mangium. Furthermore, Stachybotrys sansevieriicola is described from Sansevieria ehrenbergii (Tanzania), Phacidium grevilleae from Grevillea robusta (Uganda), Graphium jumulu from Adansonia gregorii and Ophiostoma eucalyptigena from Eucalyptus marginata (Australia), Pleurophoma ossicola from bone and Plectosphaerella populi from Populus nigra (Germany), Colletotrichum neosansevieriae from Sansevieria trifasciata, Elsinoë othonnae from Othonna quinquedentata and Zeloasperisporium cliviae (Zeloasperisporiaceae fam. nov.) from Clivia sp. (South Africa), Neodevriesia pakbiae, Phaeophleospora hymenocallidis and Phaeophleospora hymenocallidicola on leaves of a fern (Thailand), Melanconium elaeidicola from Elaeis guineensis (Indonesia), Hormonema viticola from Vitis vinifera (Canary Islands), Chlorophyllum pseudoglobossum from a grassland (India), Triadelphia disseminata from an immunocompromised patient (Saudi Arabia), Colletotrichum abscissum from Citrus (Brazil), Polyschema sclerotigenum and Phialemonium limoniforme from human patients (USA), Cadophora vitícola from Vitis vinifera (Spain), Entoloma flavovelutinum and Bolbitius aurantiorugosus from soil (Vietnam), Rhizopogon granuloflavus from soil (Cape Verde Islands), Tulasnella eremophila from Euphorbia officinarum subsp. echinus (Morocco), Verrucostoma martinicensis from Danaea elliptica (French West Indies), Metschnikowia colchici from Colchicum autumnale (Bulgaria), Thelebolus microcarpus from soil (Argentina) and Ceratocystis adelpha from Theobroma cacao (Ecuador). Myrmecridium iridis (Myrmecridiales ord. nov., Myrmecridiaceae fam. nov.) is also described from Iris sp. (The Netherlands). Novel genera include (Ascomycetes): Budhanggurabania from Cynodon dactylon (Australia), Soloacrosporiella, Xenocamarosporium, Neostrelitziana and Castanediella from Acacia mangium and Sabahriopsis from Eucalyptus brassiana (Malaysia), Readerielliopsis from basidiomata of Fuscoporia wahlbergii (French Guyana), Neoplatysporoides from Aloe ferox (Tanzania), Wojnowiciella, Chrysofolia and Neoeriomycopsis from Eucalyptus (Colombia), Neophaeomoniella from Eucalyptus globulus (USA), Pseudophaeomoniella from Olea europaea (Italy), Paraphaeomoniella from Encephalartos altensteinii, Aequabiliella, Celerioriella and Minutiella from Prunus (South Africa). Tephrocybella (Basidiomycetes) represents a novel genus from wood (Italy). Morphological and culture characteristics along with ITS DNA barcodes are provided for all taxa.