INTRODUCTION:

Throughout the last two decades, the pattern of human fungal infections has shifted considerably. People with acquired immunodeficiency syndrome (AIDS), beneficiaries of solid organ or hematopoietic stem cell transplantation (HSCT), individuals with haematological malignancies, and some other debilitated or immune-compromised people have given these illnesses a substantially higher priority. Despite the advancement in the therapy and prevention of fungal diseases, majorchanges in health-care practice haslead to the rise of newer at-risk individual populations.

Fungi are a different category of higher organisms that differ from both plants and animals in various ways. Fungal cells are first wrapped in a stiff cell wall made primarily of chitin and glucan. In contrary to the mammals, in which there are none cell walls, and plants, in which cellulose behaves as the main part of their cell walls, this is not the case. Second, unlike plants, fungi are heterotrophic, which means they cannot manufacture organic food through photosynthesis. Fungi get their food by secreting enzymes for external digestion and consuming the nutrients produced. Plants and animals have major complex type of structure as compared to the fungi. Organs and tissues do not form from the cells. There are much fewer antifungal chemicals available than there are antibacterial medications. Despite this, the number of antifungal medications is constantly expanding. The four main hemical families are polyenes, azoles, allylamines, and echinocandins. Flucytosine and griseofulvin are samples of compounds that don not conform to one of the important groups. This is not a static picture; new classes of chemicals are constantly being developed. Though certain type of infections of the fungus are having a well-defined type of symptoms, many of them remain uncommon in such a way that clinicians may overlook them. Many fungal infections, especially those in immune-compromised people, require early detection and treatment to improve disease outcomes. Clinicians may be able to establish a more comprehensive strategy to diagnosing human mycoses if they are more aware of important risk factors and clinical manifestations.

GENERAL OVERVIEW OF VARIOUS TYPES OF FUNGAL INFECTIONS:

An estimated 20-25 percent of the world's population has a fungal infection, which is most commonly a Trichophyton type of infection, making fungal disease infection one of the most common types of infection worldwide.

Deep and superficial mycoses are the two types of cutaneous infections. The majority of mycosis infections are superficial, affecting only the hair, nails, and stratum corneum of the skin. On the other hand, most of the deep type mycoses generate widespread diseases signs, which is often associated with a major type of pulmonary focus. Even though histoplasmosis, blastomycosis, and coccidiomycosis usually manifest as skin lesions, they will always be considered indications of systemic illness. Few types of deep mycosis, like the lymphangitic cutaneous sporotrichosis, primary form of cutaneous phaeohyphomycosis, and chromomycosis, are often lead by incolution into the skin directly by using a foreign body or thorn. Even cutaneous sporotrichosis can become disseminated on rare occasions. In individuals with burns, the majority of cutaneous asperigillosis infections reveal embolization of the cutaneous layer from a systemic focus.

The different types of fungal infections are being illustrated in Table 1.

Table 1. Fungal infections and their characteristics

Fungal infections	Characteristics
Superficial Mycoses
Tinea capitis	Tinea Capitis, often known as scalp ringworm, is a fungal illness caused by a variety of pathogenic dermatophytes, with the exception of Trichophyton concentricum and Epidermophyton floccosum. In the United States, most of diseases are caused by Trichophytron tonsurans, which has bypassed Microsporumaudouinii as a frequent type of pathogen. Tinea capitis is very much frequent in boys than it is in girls. The Microsporumcanis complex mostly consists of organisms that can produce minute spores that are visible from the exterior of the hair shaft. The most prevalent type of T. tonsurans carriers are non-symptomatic, and they are majorly the source of disease for siblings and peers. According to numerous research, roughly 5-15 percent of urban youngsters in Western countries have scalp dermatophytes positive cultures. The dermatophytes incidences vary widely throughout the world.
Tinea barbae	Barber's itch, commonly known as tinea sycosis, is a rare kind of ringworm that affects the beard. It affects the agriculuture working persons or to those with whom the farm animals have direct contact. It mostly affects the face and neck. There are two forms of bald patches with folliculitis: nodular, deep, suppurative lesions and crusty, superficial, partial bald patches with folliculitis. T. mentagrophytes or T. verrucosum commonly cause the deep kind of tinea barbae, which grows slowly and mostly creates thickened nodules and swellings. The overlying skin gets irritated, hairs fall out or become loose, and pus may leak from the remaining follicule openings. The crusted superficial variant of tinea barbae is related with T. rubrum and is characterised by a less inflammatory pustular folliculitis. Hairs that are impacted can sometimes be easily extracted.
Tinea facei	The fungus that causes a fungal infection in the face is frequently misdiagnosed. The annular rings are usually absent, and lesions are extremely photosensitive. The infection is beinglead by T. rubrum, M. canis, or T. mentagrophytes. Microsporumnanum, which has been found in hog farmers, is the most common cause of tinea faciei. If there is presence of fungal folliculitis, oral therapy is indicated. Only when there is no folliculitis, topical treatment used.
Tinea corporis	This tinea corporis infection primarily comprises all superficial dermatophytic skin infections that do not occur in the beard, scalp, hands, face, groin, or foot. One or more sharply delimited, circular, dry, somewhat erythematous, scaly patches, generally with hypopigmentation, are the most common symptoms of this kind of ringworm infection. The advancement of the clearing of the core region results in the formation of annular ring outlines, hence the term "ringworm." Tinea corporis can be an indication of AIDS (Acquired Immunodeficiency Syndrome), or it might be linked to the use of corticosteroids or calcineurin inhibitors.
Tinea of hands and feet	One of the most prevailing variety of fungal disease infection is dermatophytic disease of the feet, sometimes determined as athletes' foot. T. rubrum causes most of the infections. T. rubrum leads to a non-inflammatory dermatophytic disease characterised from a significant silver scaling and a boring kind of erythema that can contaminate the entire sole and foot sides, giving it a sandal-like seem. In most cases,hands tinea infection is often scaly, and erythematous, which indicates a association to T. rubrum infection. T. mentagrophytes causes tinea pedis, which has three different symptoms: multilocular bullae, which affects thin skin on the planar arch and along the sides of both the heel and the feet; desquamation and erythema between the toes; and white onchomycosis in the superficial region.
Onchomycosis (tinea unguium)	Onchomycosis is a fungal infection of the nail plate that accounts for around 30% of all superficial fungal infections. Though T. rubrum is responsible for the majority of cases, several other fungi can be involved. Other causative agents include E. flocosum and several Trichophyton and Microsporum fungus species. Onchomycosis, which is frequently caused by T. rubrum, usually begins near the nail's distal corner. A yellowish discoloration appears, which extends proximally as a nail streak. Later on, the subungual kind of hyperkeratosis becomes more noticeable and spreads to include the entire nail. Due to the accumulation of subungual keratin, the entire brittle nail gradually separates from its nailbed. Toenails and fingernails usually have a similar appearance, and the soles of the feet are more likely to develop the distinctive erythema and branny scaling.
Candidiasis	Moniliasis or candidosis are other names for the same ailment. Candida albicans is one of the most frequent bacteria found in the human genitourinary system and gastrointestinal tract. C. albicans is a pathogen that causes lesions in the nails, skin, and mucous membranes under normal circumstances. The skin's warmth, maceration, and wetness are ideal for the organism's growth. Abdominal creases, perianal and inguinal folds, inframmary creases, nailfolds, interdigital regions, and axillae are the most commonly affected sites. Candida albicans is an opportunistic organism that attacks the pathogen when the immune system is compromised or when the growth conditions are favourable. The damp and warm type of climate can lead to the growth of Candida.
Tinea versicolor	Malassezia spp. is the most common cause of tinea versicolor infection. Malassezia furfur is not the most common species isolated from lesions in clinical settings. Malassezia globosa is the most important species, but M. sympodialis, M. restricta, M. obtuse, M. furfur, and M. slooffiae have also been implicated. Infection with tinea versicolor causes hyperpigmentation or hypopigmentation, resulting in scaly macules on the upper arms and trunk. The eruption is most common in the summer and primarily affects the oily parts of the skin. The sternum and chest sides, the back, belly, neck, pubis, and intertriginous areas are all predilection spots. Around the patches, there is inflammation and a mild form of irritation. The scalp and face are the most afflicted areas. Plams, scalps, and soles are all affected by the condition. This is especially noticeable in those with darker skin tones.
Deep Mycoses
Coccidiodomycosis	Inhalation of Coccidioides posadasii or Coccidioides immitis, followed by an incubation period of 10 days to several weeks, causes a mild infection in the respiratory system, which is accompanied by a low-grade fever that resembles a flu-like sickness. It is estimated that around 60% of infected people are completely asymptomatic. High temperature, chills, nocturnal sweats, severe headache, backpain, and malaise are some of the serious symptoms that might occur in a small disease. A broad kind of eruption in the maculopapular region may develop at the time of onset, which might be confused with measles, drug eruption, or scarlet fever. The pulmonary system symptoms usually disappear after few weeks.
Cryptococcosis	In roughly 90% of patients, it starts as a pulmonary infection and then becomes a local infection in the lungs. The remaining ten percent of patients are either disabled or immune weakened. The predominant kind of Cryptococcosis pulmonary infection is also minor, and symptoms such as cough, fever, and pain may not appear. On the other hand, certain cases may be so severe that they may result in death. When dissemination occurs, the organism develops a unique affinity for the central nervous system. Cryptococcosis is the most common cause of mycotic meningitis. Hallucinations, depression, restlessness, severe headaches, nausea, vomiting, vertigo, epileptiform seizures, nuchal rigidity, and intraocular hypertension symptoms are all possible side effects. The risk factors mostly involve outdoor activities as well as exposure to bird droppings.
Mucormycosis	The Mucorales of the zygomycetes class are mostly responsible for mucormycosis infection. Invasive infections have the characteristics of being acute, developing quickly, and often lethal. There is an approximate 80 percent fatality rate in some circumstances. Patients with diabetes, leukaemia, AIDS, lymphoma, immunosuppressive iatrogenic transplanted patients, malnutrition, and chronic renal failure are all vulnerable to infections. This infection has also been linked to the use of prednisone, methotrexate, and infliximab. In most healthy people, the primary kind of cutaneous disease develops as a result of trauma, burns, or contaminated surgical dressings.
Aspergillosis	Neutropenia is the most common cause of invasive asperigillosis. Neurokinin cells play an important role in the host defence system in lymphocytes, and drugs that inhibit the immune system provide a significant danger of infection. Prolonged corticosteroid therapy, CMV infections, and GVHD infection are among the other risk factors. In individuals with reduced immunity, the majority of instances occur at the site of intravenous cannulas. Hemorrhagic bullae and necrotizing ulcers are also possible. The most common pathogen is A. flavis, which is usually linked to this infection. The patients must be treated as soon as possible so that the fungus does not spread from the skin lesion. Aspergillus fumigates is the most common cause of disseminated aspergillosis, which is linked to cutaneous involvement.

Table 2. Classification of antifungal drugs and it’s mechanism of action

Classification	Mechanism of Action
1. Drugs targeting Plasma membrane
Polyenes	The polyene Amphotericin B (AMB) works primarily by attaching to the sterol component (ergosterol) of the fungus' cell membrane. The binding results in the formation of pores with a diameter of 0.4-1.0 nm. Each pore is made up of roughly 8 AMB molecules that are hydrophobically connected to the ergosterol and have their hydroxyl groups facing inward. Perforation of the cell membrane causes cytoplasmic component leakage, suppression of aerobic and anaerobic respiration, cell lysis, and death. Nystatin, in a similar way, can cause pores to grow in the fungus' membrane, allowing potassium ions to leak out and the cell to die.Despite the fact that the development of the pore is an important mechanism of polyenes, it is a multidimensional process that can fully produce polyene activity against target cells. For example, polyenes cause oxidative damage to the fungus' plasmalemma, which contributes to the fungicidal action. AMB can also cause oxidative-dependent macrophage activation, resulting in an action that allows antifungal drugs to better engage their innate immunity.The capacity of some fungi to strategically insert ergosterols into the growth media that are competitively bound to the polyenes, thereby protecting the fungi from polyenes inhibitory effects, can be linked to their resistance to polyenes. The toxicity of polyenes is strongly dependent on the makeup of the phospholipids' fatty acyl groups; any change in the ratio of diverse phospholipids would impact the internal viscosity and lipid molecular motion within the fungal cell membrane.
Azoles	The ability of azoles to suppress CYP-450-dependent ergosterol production is largely responsible for their antifungal activity. The smooth endoplasmic reticulum of eukaryotic cells and the inner membrane of mitochondria are both made up of CYP. This structure's iron protoporphyrin moieties perform an important role in detoxification and metabolic processes. By catalysing the oxidative elimination of the 14-alpha-amethyl group of the lanosterol, CYPs are essential for the formation of ergosterol. The azole groups primarily target CYP-Erg-11-P, which can result in suppression of 14-alpha-demethylase, ergosterol depletion, and sterol precursor buildup. The replacement and depletion of ergosterol with atypical sterols usually results in changes in fluidity and membrane permeability. A nitrogen atom in the triazole or imidazole ring also plays a role in drug-iron protophyrin binding. In a similar fashion to azoles, Abafungin, which is also an antidermatophyte, can impair the synthesis of ergosterol. Itraconazole and Fluconazole inhibit the conversion of obtusifolione to obtusifoliol, resulting in the buildup of methylated sterol precursors. Luliconazole has fungicidal and fungistatic properties, as it inhibits ergosterol production and protease extracellular secretion.The azoles primarily disrupt cholesterol synthesis in animals at the 14-alpha-demthylation step. However, the dose required to inhibit CYP-dependent 14-alpha-demethylase in mammalian cells is much higher than in fungi; the concentration of Voriconazole required for inhibition of the CYP-dependent 14-alpha-demethylase in rat liver cells is about 7.4 micrometre compared to 0.03 micrometre in fungi.
Allylamines and Thiocarbamates	Thiocarbamates and allylamines often have a ring of naphthalene with an aliphatic chain replaced at one location. Napthalene inhibits fungal squalene epoxidase by a non-competitive mechanism, an enzyme that utilises nicotinamide adenine dinucleotide phosphate oxidase (NADPH) to cause squalene epoxidation to make squalene epoxide, which is a precursor to membrane ergosterol production. Butenafine hydrochloride, on the other hand, is a synthetic derivative of benzylamine that is structurally linked to synthetic allylamines, and it can disrupt ergosterol formation by inhibiting squalene epoxidase.
2. Drugs targeting cell wall
Echinocandins	Echinocandins, also known as pneumocandins, are a form of semisynthetic lipopeptide that has a cyclic core of hexapeptide and a fatty acid side chain that has antifungal properties. The FDA-approved echinocandins medications anidulafungin, caspofungin, and micafungin are primarily used to treat candidiasis and other types of mycoses infections.They are noncompetitive inhibitors that primarily target beta-1,3-glucan synthase, a 210-kDa heterodimeric protein found in the integral membrane. The terminals of budding cells that are developing are lysed, and the cells become osmotically sensitive.Because echinocandin medicines have a low bioavailability when taken orally, they can only be administered by intravenous infusions. Because of their broad spectrum of efficacy, low toxicity, and low resistance, they have become the medications of choice for treating specific kinds of mycosis alone or in conjunction with other antifungal treatments.
Caspofungin	Caspofungin was licenced for clinical usage in the year 2001 for the treatment of fungal disease in febrile neutopenic adults, patients with refractory invasive mycosis, and patients who were intolerant to AMB therapy or itraconazole therapy. It's also used to treat candidemia and other illnesses caused by the candida bacteria. The treatment lasts anywhere from one day to four months, with an average of more than one month. When compared to AMB, Caspofungin has less negative effects. Rashes, swelling of the face, pruritus, and a warm sensation have all been recorded as histamine-related symptoms that must be constantly watched. Peripheral edoema, liver injury, swelling, and hypercalcemia have all been described in extremely rare occurrences. Because there is a danger of embryotoxicity, the medicine should only be given to a pregnant woman if the benefits outweigh the risks. Negative interactions with tacrolimus and cyclosporine are also possible, thus caution should be exercised.
Micafungin	Micafungin is a naturally occurring antifungal generated by the fungus Coleophomaempetri that was cleared for clinical use by the FDA in 2005. It is mostly used to treat abscesses caused by candida, pertussis, and esophagitis. Micafungin has just been approved for use as a prophylactic in HSCT patients who are at risk of developing candidiasis. Micafungin's fungicidal action is concentration-dependent, and it also causes cell lysis and osmotic instability. Micafungin therapy can cause hypersensitivity reactions because the medicine is processed in the liver by the cytochrome-P450 enzyme.
Andidulafungin	It was previously known as LY303366, and it is a type of echinocandin that was approved by the FDA in 2006. This medicine has been shown to be effective against esophageal candidiasis and invasive candidiasis, as well as other infections caused by Aspergillus and Candida spp. Despite the fact that andidulafungin is effective against pulmonary asperigillosis, little is known regarding its efficacy in treating invasive asperigillosis in humans. Andidulafungin differs from other antifungals in that it undergoes chemical breakdown at body temperature and pH, resulting in an inactive form.
Nikkomycin	Nikkomycin and polyoxin are Streptomycete nucleoside antibiotics that block the fungus cell's chitin formation. They inhibit chitin synthase in a competitive and selective manner.Nikkomycin has a strong fungicidal action against the dimorphic type of fungi B. dermatitidis and C. immitis. The aureobasidins change chitin assembly and sphingolipid production; the medicine has a considerable antifungal effect against Candida spp. and Candida neoformans, as well as some potency against B. dermatitidis and H. capsulatum.
3. Drugs targeting nucleic acid and protein synthesis
Sordarin	Sordarin and its derivatives, such as icofungin and azosordarin, are antifungals that primarily block protein synthesis. The substance Sordarin was discovered in 1969 in a fungus called Sordariaaraneosa. It primarily slows protein synthesis by disrupting the polypeptide elongation factor (EF2) and causing tRNA displacement, as well as limiting the movement of ribosomes and mRNA. When it comes to candidiasis, azosordarin is more effective than sordarin at disrupting polypeptide chain elongation.
5-Fluorocytosine (5-FC)	5-FC disrupts protein and nucleic acid production, as well as changing the amino acid pool of sensitive cells. It first enters the cell via the cytosine permease enzyme, then is transformed to 5-fluorouracil by cytosine deaminase, and then to 5-fluorouridylic acid (5-FUMP) by uridine monophosphate pyrophosphorylase, which is subsequently phosphorylated and incorporated into RNA instead of uracil. The drug is extensively absorbed into 80S ribosomes. The widespread kind of uracil replacement by 5-FC in the RNA of the fungal cell causes changes in the amino acid pool and inhibits protein synthesis.5-FU can be transformed to 5-fluorodeoxyuridine monophosphate, which is a powerful inhibitor of the thymidylate synthase enzyme involved in DNA synthesis. In comparison to sensitive strains, resistant strains of C. neoformans incorporate the 5–FC into the RNA at low levels. In both C. neoformans and C. albicans strains, morphological modifications include a translucent and expanded type of nucleus with filamentous components, a thinner type of cell wall, and an increased type of budding. Such modifications are linked to unbalanced types of growth activities, in which DNA synthesis is terminated and the residual type of metabolism is kept.

FUTURE TRENDS OF ANTIFUNGAL THERAPY:

§ Essential oils antifungal therapy - Essential oils are complex mixes of odorous principles stored in various areas of unique plants, and they play a key role in plant defence systems against pathogenic fungus. They are made up of diverse chemical compounds with varying biological activities and therapeutic effects that can be used to control moulds and various fungi, such as food-borne and phytopathogenic fungi that cause various postharvest diseases and animal and human ailments.

Essential oil's antifungal effect is linked to phytochemical components. Furthermore, the percentage suppression of mycelia growth is affected by a number of other factors, including the antifungal activity method, observation day, oil content, and fungal species studied. The growing interest in the potential application of essential oils for pathogen management has prompted researchers to look into alternative sources of biologically active natural products in antifungal therapy in order to reduce the harmful effects of synthetic fungicidal drugs. Essential oils are volatile plant chemicals that play a vital role in plant defence mechanisms against harmful bacteria. They are a potential source of novel antifungal medicines because they are natural chemicals.

A number of research involving the use of essential oils as antifungal agents have been conducted in recent years. Fungi are known to be inhibited or killed by essential oils produced from aromatic herbs and spice plants. Molds and various fungi, such as food-borne and phytopathogenic fungi, which cause numerous postharvest diseases and animal and human ailments, have been reported to be controlled by essential oils. Various essential oils could be effective alternatives to synthetic fungicides in the treatment of plant diseases. Essential oils found in aromatic plants such as the Asteraceae, Lamiaceae, Rutaceae, and Verbenaceae show bioactivity against fungus.

§ Lipopeptides controlling fungal infections - Because of serious plant diseases caused by fungal phytopathogens and enormous economic losses, global food security has become a top priority. Lipopeptides produced by Bacillus sp. have been extensively explored in the context of bio-control of fungal phytopathogens. Surfactin, iturins, and fengycins are three families of Bacillus lipopeptides with antagonistic activity against diverse fungal phytopathogens.

Lipopeptides produced by Pseudomonas sp. have previously been shown to be efficient bio-control agents, particularly against fungal phytopathogens. Echinocandins, on the other hand, are a new class of antifungal lipopeptides produced by diverse Aspergillus species that have been successfully employed in the treatment of serious fungal infections and are currently being studied in clinical studies. We compiled all available information and data on lipopeptides with an emphasis on their usage as a bio-control agent for plant protection and in the treatment of human fungal diseases caused by various pathogenic fungi.

§ Nanocarriers as antifungal agents - Fungal infections are still a big health issue around the world. Invasive fungal infections have grown more difficult to treat in high-risk patient populations such AIDS patients, organ transplant recipients, and cancer patients receiving immunosuppressive chemotherapy.

Although superficial fungal infections are less likely to progress to systemic infection, they can be dangerous due to ineffective treatment. Controlling drug release is also critical for minimising systemic absorption and reducing the toxicity of these medicines. As a result, the administration of antifungal drugs used to treat superficial and systemic infections has a significant therapeutic and safety influence². The nanocarriers of some of the antifungal agents are clearly illustrated in Table 3.

Table 3. Nanocarriers of antifungal drugs

Antifungal drugs	Conventional type of dosage form	Nano-carriers	Reference
Clotrimazole	Cream	Micelle solution	Souto et al. (2004)³
	Solution	Solid lipid nanoparticle	Bachhav et al. (2011)⁴
Ketoconazole	Gel	Ethosome	Che et al. (2015)⁵
	Tablet	Microemulsion	Guo et al. (2015)⁶
Itraconazole	Capsule	Microemulsion	Alomrani et al. (2014)⁷
Terbinafine	Gel	Transferosome	Celebi et al. (2015)⁸
Amphotericin B	Intravenous liposomes	Nanosizing	Randhawa et al. (2015)⁹
Nystatin	Tablet	Nanosizing	Melkoumov et al. (2015)¹⁰

CONCLUSION:

Despite the large number of antifungal medications available, they fail to match the expectations for treating fungal infections, necessitating the development of novel structures with antifungal qualities that can overcome the issues of existing ones. The new antifungal drugs should have a broad spectrum of activity against fungi, including rare but medically important moulds like Scedosporium spp., Fusarium spp., and Mucorales; a better pharmacokinetic profile to reduce dosing frequency; oral and parenteral administration options; minimal side effects, and few drug-drug interactions. They should also employ novel and selective modes of action.

This review outlines the various types of fungal infections with their respective treatment. Similarly, the future trends of antifungal therapy has also been demonstrated such as the essential oils antifungal therapy, in which the essential oils play a key role in plant defence systems against pathogenic fungus. They are made up of diverse chemical compounds with varying biological activities and therapeutic effects that can be used to control moulds and various fungi, such as food-borne and phytopathogenic fungi that cause various postharvest diseases and animal and human ailments. Even the innovative nano-sized drug carriers of the antifungal drugs are critical in overcoming the constraints of traditional dosage forms to improve efficacy and treatment safety^11-20.

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

ACKNOWLEDGMENTS:

The authors would like to thank all the staff members of the Kanak Manjari Institute of Pharmaceutical Sciences, Rourkela, for providing support and all the facilities required for the study.

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Received on 20.05.2022 Modified on 13.08.2022

Asian J. Pharm. Res. 2023; 13(2):129-135.

DOI: 10.52711/2231-5691.2023.00026