Recent drug development and treatments for fungal infections

Abstract

Fungal infections are now becoming a hazard to individuals which has paved the way for research to expand the therapeutic options available. Recent advances in drug design and compound screening have also increased the pace of the development of antifungal drugs. Although several novel potential molecules are reported, those discoveries have yet to be translated from bench to bedside. Polyenes, azoles, echinocandins, and flucytosine are among the few antifungal agents that are available for the treatment of fungal infections, but such conventional therapies show certain limitations like toxicity, drug interactions, and the development of resistance which limits the utility of existing antifungals, contributing to significant mortality and morbidity. This review article focuses on the existing therapies, the challenges associated with them, and the development of new therapies, including the ongoing and recent clinical trials, for the treatment of fungal infections.

Graphical Abstract

Advancements in antifungal treatment: a graphical overview of drug development, adverse effects, and future prospects.

Introduction

Fungal infections affect approximately 1.7 billion people globally [1, 2]. Pathologically significant fungal infections can be divided into two categories: Invasive fungal infections and superficial fungal infections [3]. Thrush, oropharyngeal candidiasis, and dermatophyte infections are examples of superficial infections that affect the skin, mucous membranes, and keratinous tissues. Dermatophytes (such as Trichophyton, Microsporum, and Epidermophyton), as well as other fungi such as Malassezia spp., Candida spp., and dimorphic fungi like Sporothrix schenckii, can cause superficial fungal infections, especially in skin, nails, and hair [4]. Such superficial infections caused by fungi affect 25% of the world population, one of the major diseases being skin mycoses [5]. Conventional treatment is usually effective for such infections, but some ailments like onychomycosis have shown a very high failure rate of 25%, and recurrence is frequently reported [6]. Resistance to conventional therapies is now on an increase as seen recently in India for dermatophytoses resistant to terbinafine [7]. Conventional drugs have also caused several adverse events like liver toxicity and unwanted drug interactions [8].

Invasive fungal infections are more dangerous since they attack sterile body parts such as the bloodstream, organs (lungs, liver, and kidneys), and the central nervous system [1]. To date, there are about 5 million known species of fungus out of which 20 species are known to frequently infect human beings[9], and these species include Histoplasma capsulatum, Sporothrix spp., Candida albicans, Scedosporium, Coccidiodes immitis, Fusarium, Aspergillus fumigatus, Blastomyces dermatitidis, Candida auris, Malassezia furfur, and Cryptococcus neoformans [9, 10]. As per the findings of RCTs (Randomized Clinical Trials), the first line of treatment against Candida spp. involves the administration of echinocandins, while for Aspergillus spp., azole anti-mycotic drugs are employed [11].

Antifungal resistance is a growing concern in both clinical and agricultural settings [12, 13]. While the development of new antifungal drugs has been a crucial focus in recent years, the impact of intense antifungal use in agriculture cannot be ignored. Fungi that cause plant diseases are often treated with the same antifungal drugs used in human medicine[14]. One such example is the use of azoles, to treat fungal infections in plants such as wheat, barley, and corn [15]. Extensive use of azoles in agriculture has led to the emergence of azole-resistant strains of plant pathogenic fungi. These resistant strains can spread to other plants, and in some cases, even to humans who consume the crops[16]. Recent years have shown acquired resistance against echinocandins [17] as well as azole-resistant strains in major parts of Europe [18]. Such unregulated use of anti-fungal drugs poses a threat to public health. Widespread anti-fungal resistance has posed greater challenges to researchers and pharmaceutical companies to develop newer and more efficient alternatives. Moreover, the heterogeneity of the patients who are at risk for such invasive infections has reached a new high, such as patients who have undergone stem cell transfer or patients with chronic obstructive pulmonary disease or severe influenza [19, 20]. Therefore, the selection of the exact type of therapy to be given to such patients has become more complex. Thus, there is a pressing need to employ novel drugs which do not show any kind of resistance.

An alarming increase in the number of reported fungal infections has been caused by an increase in the number of at-risk patients and improved detection procedures [21, 22]. In the past, there was a very limited development of antifungal medications. There are mainly 4 existing classes of antifungal drugs namely: Polyenes, Azoles, Echinocandins, and flucytosine [23]. These existing classes of drugs exhibit certain disadvantages like drug resistance, variations in pharmacokinetics, toxicity, decreased bioavailability, and drug-drug interactions [24]. Antifungal medication development is difficult because fungi share a lot of eukaryotic mechanisms with humans, thus limiting the number of pathogen-specific targets. Therefore, in order to synthesize the next generation(s) of antifungal therapies, it is critical to uncover biochemical pathways unique to fungi as drug development targets. Various novel therapies with distinct mechanisms of action and the drugs that are undergoing clinical trials have been discussed in this review.

Existing anti-fungal drugs

The current anti-fungal drugs are classified into the following categories:

Antibiotics

They are further classified into:

1. Polyenes

Polyenes are the oldest family of antifungal drugs which were introduced as early as in 1950s [25]. Many polyenes have been isolated from Streptomyces spp., but only Amphotericin B (AmpB) remains in widespread use, especially with the advent of its many formulations like liposomal AmpB [26], topical nystatin [27], and AmpB lipid complex [28]. It has been known that polyenes, including Amp B which is a bigger polyene, interact with the membrane sterols, mostly ergosterol, which leads to the formation of aqueous pores. In the case of AmpB, the pore contains an annulus of 8 molecules of AmpB which is hydrophobically attached to the membrane sterols [29, 30]. This structure causes the formation of a pore in which the polyene hydroxyl is placed inward and leads to leakage of essential components of cytoplasm, modified permeation of substances, and thus leads to the death of the fungal cell [31]. Polyenes have shown a wide range of activity. They have exhibited efficiency against Candida spp., Fusarium spp., Aspergillus spp., as well as Mucorales. But at the same time, polyenes have been able to show only limited activity against Scedosporium spp [32].

• b)Echinocandins

Echinocandins are comparatively the newest antifungal class and majorly include caspofungin, anidulafungin, and micafungin. The fungal cell membrane consists of a heteromeric glycosyltransferase enzyme complex known as Beta-(1,3)-D-glucan synthase, which is primarily made of catalytic Fks p subunit and a regulatory subunit belonging to the family of Rho GTPase[33]. The regulatory and catalytic subunits are linked to the UDP-glucose and GTP, intracellularly. Echinocandins exhibit their fungicidal activity against the pathogens through non-competitive binding to the Fks p subunit of the enzyme and blocking the beta-(1,3)-D-glucan synthesis, which ultimately leads to a highly permeable and leaky cell wall and causes an imbalance in the osmotic pressure intracellularly, thus, resulting in cell lysis of the fungal cell [33]. Echinocandins show their fungicidal action against Candida ssp. and Aspergillus ssp. But they are not active against Scedosporium spp., Fusarium spp., and Cryptococcus spp. and are thus not recommended for the treatment of infections caused by these species [34].

• iii)Heterocyclic benzofuran

Griseofulvin which is a heterocyclic Benzofuran is an inhibitor of microtubule assembly [35]. It combines with microtubules to modify the synthesis of the mitotic spindle, which leads to the inhibition of mitosis in the fungal cells. By demonstrating this action, Griseofulvin acts as a fungistatic substance against various species of fungi like Epidermophyton, Microsporum, and Trichophyton [36]. But, it is not effective for the treatment of chromomycosis, dimorphic fungi, and yeast (Malassezia, Candida). Griseofulvin has a less half-life and is easily eliminated from the body; therefore, it should be administered over an extended period of time for better effectiveness [36].

Antimetabolites

5-Fluorocytosine (5FC) is the only available antimetabolite [37]. It is a fluorinated pyrimidine that exhibits anti-fungal actions against various fungal species like yeasts (Candida and Cryptococcus neoformans). The permease enzyme enables the 5FC to permeate into the fungi. As a result, the enzyme cytosine deaminase converts 5FC into 5-fluorouracil (5FU), which is then converted into 5-fluorouridylic acid (FUMP) by UMP pyrophosphorylase, and then FUMP is further phosphorylated and then inserted into the fungal RNA, thus, causing interference for the synthesis of proteins [38]. 5FU is also transformed into 5-fluorodeoxyuridine monophosphate, which causes inhibition of thymidylate synthase that plays a major role in nuclear division and synthesis of DNA [39]. Therefore, 5-fluorocytosine not only inhibits the metabolism of pyrimidine but also interferes with the synthesis of DNA, RNA, and proteins in the fungal pathogen [37]. 5-Fluorocytosine has exhibited secondary resistance which has prompted combining fluconazole or AmpB for administering the same to patients [40].

Azoles

The activity of azoles is similar to that of polyenes as they also target the fungal cell membrane. Ergosterol, which is an essential component of the fungal cell membrane, maintains its fluidity and asymmetry and thus provides integrity in the cells of fungi [41]. The lack of C-4 methyl groups in the sterols is essential for maintaining the integrity of the fungal cell membranes. Azoles mainly target the heme protein which co-catalyzes cytochrome P-450-dependent 14a-demethylation of lanosterol [42]. The degradation of the 14a-demethylase leads to the destruction of ergosterol and accumulation of the precursors of the sterol which also includes 14a-methylated sterols (24-methylenedihydrolanosterol and lanosterol, 4,14 dimethyl zymosterol), therefore, causing modifications in the structure and functions of the cell membrane. Azoles have exhibited fungicidal activity against Aspergillus spp., whereas they show fungistatic activity against Candida spp. Azoles have been effective against Cryptococcus spp.; however, they have shown mixed and limited activity against Mucorales, Scedosporium spp., and Fusarium spp [43].

Allylamines

Allylamines are a comparatively newer class of antifungals that include naftifine and terbinafine. Terbinafine is both orally and topically effective against dermatophytes (Epidermophyton spp., Microsporum, Trichophyton) and Candida. Allylamines exhibit antifungal activities by interfering with the biosynthesis of ergosterol, which also leads to the accumulation of the sterol precursor-like squalene and the absence of other intermediates of sterol; therefore, allylamines cause inhibition of synthesis of sterol during squalene epoxidation (a reaction step that catalyzes the squalene epoxidase) [44]. The death of the fungal cells is mainly associated with the accumulation of squalene than the deficiency of ergosterol. The increased amount of squalene in the fungal cells can lead to more permeation across the cell membranes [45], therefore causing interference with the cellular organization.

Terbinafine, when applied topically, causes adverse events like gastrointestinal disturbance, erythema, urticaria, rashes, neutropenia, and musculoskeletal reactions [46]. Similarly, Naftifine has known to cause mild rash, erythema, and moderate burning when applied topically in the application area [47].

Challenges of the current anti-fungal drugs

One of the major challenges of anti-fungal drug development is that of fungicide resistance. It has been reported that the rate of development of such resistance is higher than the rate of anti-fungal discovery. Fungi are known to quickly generate variants as they reproduce rapidly and because they have plastic genomes[48]. There are three major evolutionary reasons for fungicidal resistance, namely, differential survival, heritable variation, and fast reproductive output as represented briefly in Fig. 1.

Fig. 1.

Understanding the drivers of fungal adaptation to antifungal therapy

The development of antifungal drugs is undermined by the fact that fungal diseases are more closely linked to their hosts. Many key biochemical and cell biology processes are similar to fungus to humans, which explains Saccharomyces cerevisiae’s usefulness as a model eukaryotic organism [49]. As a result, many tiny compounds poisonous to yeast are toxic to humans as well. As a result, it is not astonishing that the three primary groups of antifungal medications target fungi-specific structures. In parallel to the scientific barriers that influence the recognition of novel lead compounds, the assessment of new antifungal medications has a variety of clinical trial design challenges that further hinder the advancement of novel drugs [50]. These fundamental problems, however, are in addition to the well-documented scientific, regulatory, and economic challenges that plague anti-infective development [51].

In and of itself, the limited number of antifungal medications available would not be a concern if the therapeutic results for invasive fungal infections were effective. Nevertheless, in most cases, for example, 90-day survivability after the detection of candidemia ranges from 55 to 70%, based on the patient’s general condition and the exact species that caused the infection [52]. It is worth noting that distinguishing infection-related mortality from comorbidity-related mortality is one of the most difficult aspects of examining the effects of fungal infections. Despite the usage of voriconazole, the outcomes for neutropenic cancer patients and hemato-oncologic patients are significantly worse. [53, 54].

The spectrum of activity of antifungal drugs varies, and their in vitro sensitivities are frequently examined to determine the resistance patterns of the fungal strain. Drug susceptibility screening of yeasts and filamentous fungi has lately created significant progress. The Clinical and Laboratory Standards Institute (CLSI) and the European Committee on Antimicrobial Susceptibility Testing Subcommittee on Antifungal Susceptibility Testing (EUCASTAFST) have both developed and standardized phenotypic techniques for evaluating the minimum inhibition concentration (MIC) for yeasts and conidia-forming molds. Antifungal drug resistance is typically measured using MIC values, and it has been demonstrated that when MIC values increase, treatment success rates decrease [55–57]. Primary and secondary mechanisms of antifungal drug resistance are linked to innate or evolved properties of the fungal pathogen that disrupts the antifungal action of the corresponding drug/drug class or lower target drug levels [58]. Moreover, resistance can develop when environmental circumstances cause a susceptible species to colonize or be replaced by a resistant species [59]. When a significant number of microbes are exposed to a fungistatic agent for a longer duration, acquired resistance begins to develop. Because of the rising incidence of azole-resistant strains in the surroundings, this condition is especially significant for A. fumigatus infections [59].

Antifungal drugs often have inconvenient posology [60]. Some antifungal drugs require vigilant dosing adjustments based on factors such as renal function and drug interactions. For instance, fluconazole may require a loading dose and maintenance dose due to its long half-life [61], terbinafine requires a long treatment duration and monitoring of liver function [62], and griseofulvin requires a high-fat meal for optimal absorption and can interact with other medications [63]. Similarly, the route of administration of antifungals also poses a great challenge and limits their use in certain patient populations. For example, some antifungal drugs are only available in intravenous (IV) formulations, which require hospitalization or daycare services for administration. This can be challenging for patients who cannot easily access these services, such as those living in remote areas or those with limited mobility. Furthermore, some drugs have only oral formulations available, which may limit their use in critically ill patients who cannot take medications orally [64].

Furthermore, it is worth mentioning that echinocandins, the latest class of antifungal medications, were developed in the 1970s and took 30 years to make their way into clinical practice[59]. The number of individuals at risk for fungal infections is also about to rise as medical innovation and the usage of immunomodulatory medications continue to rise. As a result, the present rate of antifungal drug discovery is unlikely to keep up with the healthcare needs, especially when resistance to existing treatments is becoming more common. Table 1 shows the existing anti-fungal drugs and their associated adverse events which call for more research and development in the field of antifungal drug discovery.

Table 1.

An overview of the existing antifungal medications, including information on their mode of action, spectrum of activity, and associated adverse events

Class of drugs	Mechanism of action	Existing anti-fungal drugs	Spectrum of activity	Adverse events	References
Polyenes	Binds to ergosterol in the fungal cell membrane, causing leakage of intracellular contents	Amphotericin B	Broad spectrum: Candida species (including C. albicans, C. parapsilosis, and C. tropicalis, C. krusei, C. kefyr, C. famata, C. guilliermondii), Aspergillus species (including A. fumigatus, A. flavus, A. terreus, A. niger), Cryptococcus neoformans, Histoplasma capsulatum, Blastomyces dermatitidis, Coccidioides immitis, Paracoccidioides brasiliensis, Paecilomyces sp., Penicillium sp., Fusarium sp., Bipolaris sp., Exophiala sp., Cladophialophora sp., Absidia sp., Apophysomyces sp., Mucor sp., Rhizomucor sp., Saksenaea sp. Talaromyces marneffei	Infusion-related toxicity, hypertension/hypotension, hypoxia, hyperkalemia, cardiac toxicity nephrotoxicity, anemia	Walsh et al., [65]; Hoeprich PD., [66]; Anderson CM., [67]
		Nystatin	Broad spectrum: Candida species (including C. albicans, C. glabrata, and C. tropicalis), Aspergillus species, Cryptococcus neoformans	Gastrointestinal adverse reactions, including vomiting, nausea, diarrhea, anorexia, and abdominal pain	Hoppe JE., [68]; Flynn PM., [69]; Pons V et al., [70]; Blomgren J et al., [71]
Echinocandins	Inhibit the synthesis of β-(1,3)-D-glucan, a key component of fungal cell wall	Caspofungin	Candida species (including C. albicans, C. glabrata, and C. tropicalis), Aspergillus species (including A. fumigatus and A. flavus), Histoplasma capsulatum, Blastomyces dermatitidis	Phlebitis/thrombophlebitis, tachycardia, hepatitis, hepatomegaly, hyperbilirubinemia	Keating and Figgit., [72]; Fotsing, L.N.D. and Bajaj, T., [73]
		Micafungin	Broad spectrum: Candida species (including Candida albicans, Candida tropicalis, and Candida parapsilosis), Aspergillus species (including Aspergillus fumigatus), and some dimorphic fungi (such as Histoplasma capsulatum)	Neutropenia, nausea, diarrhea, hyperbilirubinemia, hypokalemia	Eschenauer et al., [74]
		Anidulafungin	Broad spectrum: Candida species (including C. albicans, C. tropicalis, and C. parapsilosis), and Aspergillus species (including Aspergillus fumigatus)	Neutropenia, leukopenia, nausea, dyspepsia, hypokalemia, rash, pyrexia	Eschenauer et al., [74]
Heterocyclic benzofuran	It is taken up by fungal cells and converted into 5fluorouracil, followed by conversion to 5fluorodeoxyuridylic acid, an inhibitor of thymidylate synthesis	Griseofulvin	Narrow spectrum: dermatophytes (including Trichophyton species, Microsporum species, and Epidermophyton floccosum)	Gastrointestinal adverse reactions, photosensitivity, fixed drug eruption, petechiae, pruritus, and urticaria, elevated triglycerides, anemia	Gupta et al., [75]; Kreijkamp-Kaspers et al., [76]; Chaudhary et al., [77]
Antimetabolite	Interferes with fungal nucleic acid synthesis	Flucytosine	Narrow spectrum: Candida species (including C. albicans, C. glabrata, C. tropicalis, and C. parapsilosis), and Cryptococcus neoformans	Gastrointestinal adverse effects, rash, pruritus, acute hepatitis nephrotoxicity, myelotoxicity	Folk et al., [78]
Azoles (Imidazoles)	Inhibits the activity of the fungal enzyme cytochrome P450-dependent 14-alpha-sterol demethylase (CYP51), which is responsible for converting lanosterol into ergosterol, a key component of the fungal cell membrane. They inhibit a broader range of CYP enzymes, including human CYP enzymes, which can lead to more drug interactions and adverse effects	Clotrimazole	Broad spectrum: Candida species (including C. albicans, C. glabrata, C. tropicalis, C. krusei, C. parapsilosis, C. guilliermondii, and C. lusitaniae), and some dermatophytes (such as Trichophyton mentagrophytes and Trichophyton rubrum)	Abnormal liver function tests, rash, hives, blisters, burning, itching, peeling, redness, swelling, pain, or other signs of skin irritation	Jelen and Tennstedt., [79]
		Econazole	Broad spectrum: Candida species (including C. albicans, C. glabrata, C. tropicalis, C. krusei), dermatophytes (including Trichophyton species, Microsporum species, and Epidermophyton floccosum), Malassezia furfur	Irritation, redness, burning, or itching	Heel et al., [80]
		Miconazole	Broad spectrum: Candida species (including C. albicans, C. glabrata, C. tropicalis, C. krusei), dermatophytes (including Trichophyton species, Microsporum species, and Epidermophyton floccosum), Malassezia furfur	Thrombocytopenic purpura, acute gastroenteritis	Yan et al., [81]
		Sulconazale	Broad spectrum: dermatophytes (including Trichophyton species, Microsporum species, and Epidermophyton floccosum), Candida albicans	Redness, irritation, contact dermatitis, and pruritus	Benfield and Stephen., [82]
		Ketoconazole	Broad spectrum: Candida species (including C. albicans, C. glabrata, C. tropicalis, C. krusei), dermatophytes (including Trichophyton species, Microsporum species, and Epidermophyton floccosum), Malassezia furfur	Gastrointestinal side effects, orthostatic hypotension, gynecomastia in males, severe liver injury, and jaundice	Sohn CA., [83]; Gupta and Lyons., [84]; Brass et al., [85]
Azoles (Triazoles)	Selectively inhibits the fungal CYP51 enzyme, resulting in decreased ergosterol synthesis and accumulation of toxic sterols in the fungal cell membrane	Fluconazole	Broad spectrum: Candida species (including C. albicans, C. glabrata, C. tropicalis, C. krusei, C. parapsilosis), Cryptococcus neoformans, Coccidioides spp.	Gastrointestinal symptoms, anaphylaxis, hepatotoxicity, asthenia, myalgia, Stevens-Johnson syndrome and toxic epidermal necrolysis, alopecia, and chapped lips	Amichai and Grunwald., [86]; Pappas et al., [87]
		Itraconazole	Broad spectrum: Candida species (including C. albicans, C. glabrata, C. tropicalis, C. krusei, C. parapsilosis), Aspergillus species (including A. fumigatus, A. flavus, A. niger, A. terreus), Blastomyces dermatitidis, Histoplasma capsulatum, Sporothrix schenckii, Paracoccidioides brasiliensis, Coccidioides spp., Talaromyces marneffei, Histoplasma capsulatum	Cardiotoxicity, gastrointestinal disturbances	Piérard et al., [88]; Abraham and Panda., [89]
		Voriconazole	Broad spectrum: Candida species (including C. albicans, C. glabrata, C. tropicalis, C. krusei, C. parapsilosis), Aspergillus species (including A. fumigatus, A. flavus, A. niger, A. terreus, and A. nidulans), Scedosporium apiospermum, Fusarium species, Histoplasma capsulatum, Coccidioides spp., Talaromyces marneffei	Hepatotoxicity, visual disturbances, and phototoxicity	Re III et al., [90]; Raschi et al., [91]; Saravolatz et al., [92]; Epaulard et al., [93]
		Posaconazole	Broad spectrum: Candida species (including C. albicans, C. glabrata, C. tropicalis, C. krusei, C. parapsilosis), Aspergillus species (including A. fumigatus, A. flavus, A. niger, A. terreus, and A. nidulans), Scedosporium species, Fusarium species, Zygomycetes (including Rhizopus, Mucor, and Absidia species)	Headache, fatigue, QT prolongation, atrial fibrillation, a decreased ejection fraction, and torsades de pointes	Courtney et al., [94]; Cornely et al., [95]
Allylamine	Inhibits squalene epoxidase, an enzyme involved in the biosynthesis of ergosterol	Terbinafine	Broad spectrum: dermatophytes (including Trichophyton species, Microsporum species, and Epidermophyton floccosum), some dimorphic fungi (including Histoplasma capsulatum and Coccidioides immitis)	Gastrointestinal symptoms, rash, urticaria, erythema, visual disturbances, dysgeusia, and mild transaminitis	Lipner and Scher., [96]; Zane et al., [97]
		Naftifine	Broad spectrum: dermatophytes (including Trichophyton species, Microsporum species)	Mild and transient burning, itching, and stinging	Gupta et al., [98]

Novel anti-fungal drugs

In recent decades, there has been minimal progress in the development of novel antifungal drugs [99]. For instance, since Isavuconazole, a third-generation triazole, was approved by the US Food and Drug Administration (FDA) in 2015 (Miceli and Kauffman, [100]) (Fig. 2), only two new drugs have been approved by FDA, namely Oteseconazole (April 2022) [101] and Ibrexafungerp (June 2021) [102]. The genetic and metabolic commonalities between fungal and human cells make it challenging to develop new antifungal medications, making it difficult to uncover specific new fungal targets [99]. As a result, the 3 main classes of antifungal agents that are in use for medical practice have been targeted as structures and metabolic processes that are solely produced by fungi: ergosterol and its biosynthesis pathway, as well as -(1,3)-glucan production. The most common technique used for antifungal medication development is to increase the therapeutic index of presently accessible antifungal drugs by modifying them chemically and developing novel formulations to produce the least toxic compounds [100, 103].

Fig. 2.

An infographic of the antifungal pipeline highlighting the most promising drug candidates and their development timelines

In recent years, various potential antifungal drugs have been patented. Corifungin, a water-soluble sodium salt of AmpB generated by fermentation of Streptomyces nodosus strain NRRLB2371, was patented by ACEA Biotech Inc. (USA) and has wide antifungal functions both in vitro and in vivo [104]. Antimicrobial peptides (AMPs) are cationic peptides and are of low molecular weight. They are produced by plants, vertebrates, and invertebrates as part of their innate immune response [105]. C3 Jian (USA) developed a unique set of structures created by several functional domains with action against yeasts and filamentous fungi, by employing a broad spectrum of antibacterial capabilities of AMPs [106]. Similarly, the Wisconsin Alumni Research Foundation (USA) has patented a number of beta-peptides that contain cyclically restricted -amino acid residues with helical conformations and exhibit significant in vitro action against both planktonic and biofilm-forming C. albicans cells [106].

Polichem SA, Luxembourg (Switzerland), patented chemically synthesized derivatives from 8-hydroxyquinoline-7-carboxamide that exhibited remarkable action against yeasts and filamentous fungus via iron chelation (Stefania et al., 2015). The quinazolinone derivatives patented by F2G Limited (Great Britain), which block the fungal enzyme dihydroorotate dehydrogenase (DHODH) and exhibit better effectiveness against Aspergillus spp., are another synthetic drug with a unique mode of action [107]. A sequence of pyrrole derivatives with remarkable in vitro action against filamentous fungus and the ability to improve survivability in murine models of disseminated aspergillosis was also patented by the same company. Janssen Pharmaceutical (Belgium) synthesized and patented synthetic derivatives of pyrrolo[1,2α][1,4]-benzodiazepine substituted with bicyclic benzene rings to combat dermatophytes and species that cause systemic illnesses and, thus, resulting in enhanced bioavailability and metabolic stability [106].

Olorofim is the premier candidate drug of the orotomides, which is a novel class of antifungal agents. Orotomides demonstrate a unique mode of action by causing inhibition of the dihydroorotate dehydrogenase (DHODH) [108], which is an important enzyme involved in the biosynthesis of pyrimidine. Pyrimidine is a vital component in the synthesis of DNA, RNA, cell wall, and phospholipids, as well as in cell control and protein synthesis [109]; therefore, the inhibition of the biosynthesis of pyrimidine will significantly affect the fungal pathogen. The DHODH-target enzyme is not found in many of the fungal species, but the variations in its structure account for its various susceptibilities [108]. Due to the effective bioavailability of Olorofim, it can be administered through the oral and intravenous (I.V) route. Currently, only the oral dosage form is being tested, but the I.V. formulation will be soon available. The substance is found in many tissues, like in the kidney, liver, lung, as well as in brain, though in lesser amounts in the latter [108]. Orolofim demonstrated fungistatic activities against Aspergillus spp. at the initial stage, but after prolonged exposure, it exhibited fungicidal actions [110]. Olorofim also exhibits antifungal actions against various molds which includes Lomentospora prolificans, for which there is no current treatment available [111, 112] But, Olorofim does not exhibit any actions against Cryptococcus neoformans, Mucorales spp., and Candida spp. because of differences in the targeting of the site of infection by the drug [113].

In addition, tetrazoles like VT-1129 and VT-1598 have come into the picture, especially with the FDA approval of VT-1161 recently in 2022 for the treatment of vulvovaginal candidiasis [101]. VT-1161, also known as Oteseconazole, is administered orally to reduce the incidence of recurrent vulvovaginal candidiasis in females who are not of reproductive potential. VT-1598, another next-generation azole, shows a very broad spectrum of in vitro activity against C. auris, molds, as well as endemic fungi like Blastomyces dermatitidis, Histoplasma capsulatum, C. immitis, and Coccidioides posadasii [111, 114]. It has been granted QIDP (Qualified Infectious Disease Product), fast track, and orphan drug designation for the treatment of coccidioidomycosis by the FDA. Fosmanogepix (previously known as APX001) inhibits the GPI-anchored wall protein transfer 1. It has been known to show potent in vitro activity against Candida species, especially the echinocandin-resistant C. albicans and C. glabrata [115]. Clinical development has so far focused on its development in infections caused by Candida spp., Aspergillus spp., and some rare molds. Eyeing the recent clinical developments, the FDA has given fast track, QIDP, and orphan drug designation to fosmanogepix. Another novel anti-fungal drug, Rezafungin (previously called CD101), is from the echinocandin class of drugs. It is essentially a structural analogue of anidulafungin with a choline moiety at the C5 position, which gives it increased solubility and stability [116]. It has shown activity against WT (wild type) and azole-resistant Candida species and Aspergillus spp. [117, 118]. The FDA has provided Rezafungin fast track and QIDP designation for the prevention of fungal infections. In addition to this, the FDA has granted fast track, QIDP, and orphan drug designation for the treatment of invasive candidiasis. One of the major upcoming candidates is the encochleated AmB (CAMB), which is a novel formulation intended for oral administration. Cochleates assemble to form a multilayering composed of an array of phosphatidylserine (negatively charged lipid) and a divalent cation (Calcium). This structure protects against the degradation of AmB in the gut [119]. CAMB has also been granted fast track, QIDP, and orphan drug designation by the FDA.

While antifungal drug development is not always driven by the needs of endemic systemic mycoses, it is important to consider the role of new drugs in addressing these diseases. Diseases such as histoplasmosis, coccidioidomycosis, and talaromycosis are serious fungal infections that lack effective treatments [120]. The recent drug development efforts have yielded several new drugs that have shown promise in treating these infections [121]. For example, isavuconazole and voriconazole are now considered first-line therapies for invasive aspergillosis, which is a common complication of some endemic mycoses [122, 123]. In addition, new drugs such as fosmanogepix and VT-1598 have shown efficacy against a broad range of fungal pathogens, including those causing endemic systemic mycoses [121, 123].

Some of the novel antifungal drugs that have completed or are undergoing clinical trials are listed in Table 2. These drugs are being tested against a range of fungal infections, including serious conditions such as aspergillosis and cryptococcal infections, as well as less severe conditions such as vulvovaginal candidiasis, onychomycosis, and tinea pedis. The main goal of these clinical trials is to overcome the disadvantages that are associated with the treatment of resistant and recurrent fungal infections and additionally demonstrate better safety, efficacy, tolerance, broad spectrum of activity, and fewer drug-drug interactions.

Table 2.

Recently completed and currently undergoing clinical trials of novel antifungal drugs

Agents	Class of drugs	Study title	Condition (s)	Intervention	Study initiation date	Date of completion	Study phase/type	NCT number	Inference*	Status
Oteseconazole (VT-1161)	Azoles	A Study of Oral Oteseconazole (VT-1161) for the Treatment of Patients with Recurrent Vaginal Candidiasis (Yeast Infection) (VIOLET)	Recurrent vulvovaginal candidiasis	Drug: VT-1161 VT-1161 150 mg capsule Placebo matching capsule	August 23, 2018	August 3, 2021	Phase-3	NCT03561701	A higher value of efficacy was achieved in patients receiving VT-1161 when compared with the placebo group	Approved by FDA on 1st April 2022 for the treatment of recurrent vulvovaginal candidiasis (RVVC)
		Study of Oral Oteseconazole (VT-1161) for Acute Yeast Infections in Patients with Recurrent Yeast Infections (ultraVIOLET)	Recurrent vulvovaginal candidiasis	Drug: Oteseconazole (VT-1161) 150 mg capsule Drug: Fluconazole 150 mg capsule Drug: Placebo	March 13, 2019	December 2, 2020	Phase-3	NCT03840616	Oteseconazole was found to be more efficacious than Fluconazole/Placebo. Some non-serious adverse events like nausea, pyrexia, UTI, bacterial vaginosis, sinusitis, headache, and rash were observed
		A Study to Evaluate Oral VT-1161 in the Treatment of Patients with Recurrent Vaginal Candidiasis (Yeast Infection)	Recurrent vulvovaginal candidiasis	Drug: VT-1161 Drug: Placebo	February 10, 2015	November 9, 2016	Phase-2	NCT02267382	VT-1161 was well-tolerated and exhibited a good safety profile. Adverse event incidence in the VT-1161 arm was much lower than that of the placebo. Overall, it was proved to be more efficacious than placebo
		A Study to Assess the Efficacy and Safety of Oral VT-1161 in Patients with Toenail Onychomycosis	Onychomycosis	Drug: VT-1161 Placebo	February 17, 2015	July 7, 2017	Phase-2	NCT02267356	An effective nail clearance rate was seen after treatment with VT-1161
		Oral VT-1161 Efficacy and Safety in Patients with Moderate to Severe Interdigital Tinea Pedis	Tinea Pedis	Drug: VT-1161 placebo	August 2013	December 2014	Phase-2	NCT01891305	Clinical and mycological cure was achieved in patients receiving VT-1161, while none of the patients in the placebo group could recover. No mortality was reported. Non-serious adverse events included Herpes Zoster and influenza
Rezafungin (CD 101)	Echinocandins (Antibiotics)	CD101 Compared to Caspofungin Followed by Oral Step Down in Subjects with Candidemia and/or Invasive Candidiasis-Bridging Extension	-Candidemia -Mycoses -Fungemia -Invasive Candidiasis	Drug: CD101 Drug: Caspofungin Drug: Fluconazole Drug: intravenous placebo Drug: oral placebo	July 26, 2016	July 2019	Phase-2	NCT02734862	The drug showed safety, efficacy, and tolerability while being administered once a week when compared with once-daily CAS plus fluconazole for the treatment of candidemia and invasive candidiasis	FDA has granted fast track and QIDP designation for the prevention of fungal infections. Also, it has been granted fast track, QIDP, and orphan drug designation for the treatment of invasive candidiasis
		Study of Rezafungin Compared to Standard Antimicrobial Regimen for Prevention of Invasive Fungal Diseases in Adults Undergoing Allogeneic Blood and Marrow Transplantation (ReSPECT)	Candidemia Mycoses Fungal Infection Fungemia Invasive Candidiasis Pneumocystis Mold Infection Invasive Fungal Disease Prophylaxis of Invasive Fungal Infections Aspergillus	Drug: Rezafungin for Injection Drug: Posaconazole Drug: Fluconazole Drug: Trimethoprimsulfamethoxazole (TMP/SMX) Drug: Intravenous Placebo Drug: Oral Placebo	May 11, 2020	March, 2022	Phase 3	NCT04368559	Recruitment in process
MAT2203 (Encochleated Amphotericin B)	Novel nanoparticle-based encochleated AmB (CAmB) formulation	Oral Encochleated Amphotericin B (CAMB/MAT2203) in the Treatment of Vulvovaginal Candidiasis (VVC): Safety and Efficacy	-Vulvovaginitis -Yeast infection -Vaginal candidiasis, vulvovaginal	Drug: Oral Encochleated Amphotericin B (CAMB) lipid-crystal nano-particle formulation amphotericin B Other name: MAT2203 Drug: Fluconazole	November 2016	May 2017	Phase-2	NCT02971007	A higher percentage of mycological eradication was seen in patients administered with Fluconazole when compared with CAMB. Clinical cure was achieved in a greater percentage of patients in the Fluconazole group compared to the CAMB group. No mortality was reported in any of the groups. Non-serious adverse events included diarrhea, nausea, bacterial vaginosis, and urinary tract infection	The FDA granted MAT2203 as a Qualified Infectious Disease Product (QIDP) with fast track status, with the potential for Orphan Drug Designation
		CAMB/MAT2203 in Patients with Mucocutaneous Candidiasis (CAMB)	Candidiasis, chronic mucocutaneous	Drug: Amphotericin B	September 2016	December 31, 2022	Phase-2	NCT02629419	Oral CAMB was able to reduce vaginal and tongue fungal load. The drug showed good efficacy with high tolerability and safety
		Encochleated Oral Amphotericin for Cryptococcal Meningitis Trial (EnACT) (EnACT)	Cryptococcal meningitis	Drug: MAT2203 Drug: Amphotericin B	October 24, 2019	October 2022	Phase-1 Phase-2	NCT04031833	Oral CAMB showed a good safety profile and was well-tolerated when compared with IV amphotericin B
Fosmanogepix (APX001)	Glycosyl phosphatidylinositol (GPI) inhibitor	A Study to Learn About the Study Medicine (Called Fosmanogepix/ PF-07842805) in People with Candidemia and/or Invasive Candidiasis	Candidemia candidiasis, invasive	Drug: PF-07842805 Drug: Caspofungin Drug: Fluconazole Drug: Placebo	December 5, 2022	February 10, 2026	Phase 3	NCT05421858	Recruitment has not started yet	The FDA has granted fast track, Qualified Infectious Disease Product (QIDP), and orphan drug designation to fosmanogepix for the treatment of invasive candidiasis, scedosporiosis, fusariosis, coccidioidomycosis, invasive aspergillosis, and mucormycosis, cryptococcosis
		Open-label Study of APX001 for Treatment of Patients with Invasive Mold Infections Caused by Aspergillus or Rare Molds (AEGIS)	Invasive fungal infections	Drug: fosmanogepix	January 4, 2020	October 2021	Phase 2	NCT04240886	Currently recruiting
		An Efficacy and Safety Study of APX001 in Non-Neutropenic Patients with Candidemia	Candidemia	Drug: APX001	October 3, 2018	July 2, 2020	Phase 2	NCT03604705	Overall, 80% treatment success was achieved. Mortality of 23.81% was observed. Serious adverse events were seen including cardio-respiratory arrest, septic shock, bacteraemia, necrotising fasciitis, urinary tract infection, among others. Non-serious adverse events like diarrhea, nausea, vomiting, pyrexia, hydronephrosis, pleural effusion and dyspnea were also observed
Olorofim (F901318)	Orotomides acts by inhibition of dihydroorotate dehydrogenase	Olorofim Aspergillus Infection Study (OASIS)	Invasive aspergillosis	Drug: Olorofim Drug: AmBisome®	November 30, 2021	March 4, 2025	Phase 3	NCT05101187	Recruitment has not started yet	The FDA granted orphan drug and breakthrough therapy designation. Orphan drug designation also granted by The European Medicine Agency Committee for Orphan Medicinal Products
		Evaluate F901318 Treatment of Invasive Fungal Infections in Patients Lacking Treatment Options (FORMULA-OLS)	Invasive fungal infections	Drug: F901318	June 6, 2018	April 2023	Phase 2	NCT03583164	Currently recruiting
Ibrexafungerp (SCY-078)	Glucan synthase inhibitor	Coadministration of Ibrexafungerp (SCY-078) with Voriconazole in Patients with Invasive Pulmonary Aspergillosis: A Safety and Efficacy Study	Invasive pulmonary aspergillosis	Drug: SCY-078 Oral tablets of SCY-078 Other name: Ibrexafungerp Drug: Voriconazole Voriconazole IV vials or oral tablets Other: Oral Placebo Tablets Oral Placebo Tablets matching SCY-078 Other name: SCY-078 matching Placebo	January 22, 2019	November 26, 2022	Phase-2	NCT03672292	Recruiting in process	FDA approved on June 1, 2021, for 1-day oral treatment of vaginal yeast infection
		Dose-Finding Study of Oral Ibrexafungep (SCY-078) vs. Oral Fluconazole in Subjects with Acute Vulvovaginal Candidiasis (DOVE)	Candida vulvovaginitis	Drug: Fluconazole Drug: SCY-078	August 1, 2017	May 4, 2018	Phase-2	NCT03253094	Ibexafungerp was well-tolerated and exhibited a good safety profile. The most common adverse events seen were only mild gastrointestinal events. Overall, it showed comparable efficacy to fluconazole
		Efficacy and Safety of Oral Ibrexafungerp (SCY-078) vs. Placebo in Subjects with Acute Vulvovaginal Candidiasis (VANISH 303)	Candida vulvovaginitis	Drug: Ibrexafungerp Drug: Placebo	January 4, 2019	September 4, 2019	Phase-3	NCT03734991	The overall success percentage of Ibrexafungerp was found to be better than placebo. No mortality was observed. One patient developed pneumonia and bronchial hyperactivity. Some non-serious adverse events include diarrhea, nausea, bacterial vaginosis, headache, and abdominal pain
		Open-Label Trial to Assess the Efficacy and Safety of Oral Ibrexafungerp (SCY-078) in Patients with Candida Auris-Induced Candidiasis (CARES)	-Candidiasis, invasive -Candidemia	Drug: SCY-078 Oral SCY-078	November 15, 2017	December 15, 2022	Phase-3	NCT03363841	Recruiting in process
		Oral Ibrexafungerp (SCY-078) Efficacy and Safety vs. Placebo in Subjects with Acute Vulvovaginal Candidiasis	Candida vulvovaginitis	Drug: Ibrexafungerp Ibrexafungerp 300 mg BID for 1 day Other name: SCY-078 Drug: Placebo Matching Placebo	July 7, 2019	April 29, 2020	Phase-3	NCT03987620	Successful clinical cure was achieved when compared with the placebo group. No adverse events that lead to death of the patients were reported. Non-serious adverse events like headache, nausea, and diarrhea were observed
		Ibrexafungerp for the Treatment of Complicated Vilvovaginal Candidiasis	Candida vulvovaginitis	Drug: Ibrexafungerp Ibrexafungerp 150 mg BID	May 1, 2022	November 30. 2024	Phase 3	NCT05399641	Recruitment in process. No results posted yet
		Efficacy and Safety of Oral Ibrexafungerp (SCY-078) vs. Placebo in Subjects with Acute Vulvovaginal Candidiasis (Vanish 306)	Candida vulvovaginitis	Drug: Ibrexafungerp Placebo	June 7, 2019	April 29, 2020	Phase 3	NCT03987620	Higher percentage of clinical cure was reported among patients receiving Ibrexafungerp when compared with the placebo group. No mortality was reported. Out of 298 patients, only 1 serious adverse event was observed
		Study to Evaluate the Efficacy and Safety of Ibrexafungerp in Patients with Fungal Diseases That Are Refractory to or Intolerant of Standard Antifungal Treatment (FURI)	Invasive candidiasis, mucocutaneous candidiasis, coccidioidomycosis, histoplasmosis, blastomycosis, chronic pulmonary aspergillosis, allergic bronchopulmonary aspergillosis, invasive pulmonary aspergillosis, recurrent vulvovaginal candidiasis, other emerging fungi	Drug: Ibrexafungerp	April 1, 2017	December, 2022	Phase 3	NCT03059992	Recruitment in process

^*Table does not include data from clinical trials that have been withdrawn, terminated or which have completed the recruitment process but no results have been posted as yet

Conclusion and future perspectives

The increasing prevalence of invasive fungal infections, drug resistance, and adverse effects associated with current antifungal medications highlight the urgent need for novel therapies in the fungal domain. Although, due to the aforementioned reasons, it is not so simple to synthesize antifungal drugs, there are various agents that are in the end phase of development. Few of them demonstrate enhanced resistance profiles like Olorofim and SCY-078. The rest of the agents exhibit a primary benefit in the formulation and administration like MAT2203, SCY-078, and CD101. Additionally, Isavuconazole has more advantages compared to voriconazole due to its better safety profile, efficacy, fewer drug-drug interactions, and the fact that routine therapeutic drug monitoring is typically not required for isavuconazole, whereas voriconazole requires TDM to ensure safe and effective dosing [124, 125]. Lately, the novel class of antifungal drugs- Orotomides demonstrate less cross-resistance and enables administration through the oral route.

Various antifungal compounds are still undergoing development and are under pre-clinical and clinical trials. But more research is still necessary during the post-marketing phase to evaluate the safety, efficacy, and resistance in various populations. Other than that, more studies should be conducted to develop novel therapeutic strategies for fungal infections, for example, repurposing of medications, antifungal biological substances, and host-immune cell-targeted strategies.

Novel formulations and drug delivery systems for currently used antifungal medications can, in fact, allow the synthesis of therapeutic targets, which should result in better efficacy and lower toxicity, as well as better health outcomes. The same can be said for antifungal pharmacokinetic/pharmacodynamic (PK/PD) concepts, where improved in vitro and in vivo PK/PD models, more precise medicinal antifungal PK/PD assumptions, and therapeutic evaluation can contribute to improvement in antifungal dosage and a higher chance of a positive outcome for individuals suffering from fungal infections.

For the past few years, there has also been a surge in research for repurposing as a way to speed up the development of antifungal drugs. Repurposing, which is also known as repositioning, involves the exploration of new therapeutic applications for existing medications, as opposed to the hard, protracted, and costly proposition of de novo drug creation. Repurposing enables the recognition of pharmaceuticals with established PK, PD, and safety profiles in individuals, which is affordable, faster, and more likely to succeed than the conventional discovery of novel drugs. As a result, repurposing studies can result in a rapid introduction of innovative antifungal medications, reducing the time between lab and patient. This is especially relevant in the case of multidrug-resistant and rising diseases, as evidenced by the recent rapid expansion of C. auris infections. The literature has numerous examples of research focused at the repurposing of current medications into antifungals [126–130]. These initiatives have actually employed the use of the accessibility of repurposing libraries, which are collections of many current medications that can be quickly searched for compounds with unique antifungal activity [131–138]. Moreover, the development of novel biopharmaceuticals for antifungal therapy has paved way for the possibility of novel alternate strategies especially keeping in mind the host–pathogen response. Above all, major considerations should be drawn upon the patient, who is in actual need of medication and support to cure the infection without hampering the quality of life.

Data availability

All data generated or analyzed during this study are included in this published article.

Declarations

Conflict of interest

The authors declare no competing interests.