Introduction
Mycetoma is a WHO recognised neglected tropical disease that is a subcutaneous chronic
granulomatous progressively morbid inflammatory disease [1]. It frequently affects
young adults and children in remote rural areas. It most commonly affects field laborers
and herdsmen who are in direct contact with the soil. Hence, the most common site
of infection is the foot, and the hand ranks second. Less frequently, other parts
of the body may also be infected [2].
The disease can either be caused by true fungi, so called eumycetoma, or by certain
bacteria, so called actinomycetoma, and the common causative organisms are Madurella
mycetomatis and Nocardia brasiliensis, respectively [3,4]. These organisms are thought
to be present in the soil, thorns, or animal dunk, and they are probably implanted
into the host subcutaneous tissue through a breach in the skin as a result of minor
trauma [5].
Mycetoma, irrespective of the aetiological agent, presents as a slowly progressive,
painless, subcutaneous swelling. Multiple secondary nodules then evolve that may suppurate
and drain through multiple sinuses tracts. The sinuses usually discharge grains containing
colonies of the causative organism, and they are considered as a unique characteristic
of the disease (Fig 1) [6,7].
10.1371/journal.pntd.0008307.g001
Fig 1
A massive eumycetoma lesion with multiple discharging sinuses and black grains.
Actinomycetoma is relatively more responsive to medical treatment, which depends on
the site, the severity of the disease, and the causative organisms, with a cure rate
of up to 90% [8]. In contrast, treatment of eumycetoma is challenging and problematic,
of which most cases do not respond to medical therapy alone and require alongside
surgical intervention. In general, the treatment outcome of eumycetoma is suboptimal
and unsatisfactory in many patients [9,10].
The disease then spreads to involve the skin, subcutaneous tissue, deep structures,
and bone, resulting in destruction, deformity, loss of function, and, occasionally,
mortality [7].
This Review highlights the currently available treatment options for eumycetoma caused
by M. mycetomatis and their shortcomings, possible factors contributing to treatment
failure, and prospects for achieving better treatment outcomes.
Diagnosis of eumycetoma
The appropriate treatment of mycetoma depends on precise identification of the causative
agent to the species level and the disease extent. For the latter, many imaging techniques
are required, and include conventional X-ray radiography, ultrasonography, computed
tomography (CT), and magnetic resonance imaging (MRI) [11–15]. Molecular techniques
such as species-specific polymerase chain reaction (PCR), serodiagnosis as ELISA,
and counter-immunoelectrophoresis as well as the classical grain culture and surgical
biopsy histopathological examination are all needed to achieve accurate organism identification
[11,16–18]. These techniques are not only important for diagnosis, but they also aid
in treatment follow-up and assessment of cure. However, most of these techniques are
invasive, expensive, of low sensitivity and specificity, and not available in endemic
regions, and, hence, there is a desperate need for developing simple tests and point
of care diagnostic tools.
Treatment of eumycetoma
Despite centuries of recognition, the treatment of eumycetoma remains challenging,
difficult, and disappointing. Until now, there are no definite treatment guidelines
or protocols. Therefore, the treatment is based on personal experiences or a few published
case reports and case series [9,10].
Currently, the treatment starts with preoperative antifungal treatment for six months,
which continues postoperatively for at least six months [9,10]. Surgical intervention
is usually in the form of adequate wide local excision, repeated aggressive debulking
and debridement, or amputation in advanced disease. It aims to reduce the lesion size
for better response to medical treatment or complete removal of the bacterial infected
lesion [19]. The adjunct antifungal treatment is always necessary to localise the
disease by forming a thick capsule around the lesion which facilitates the surgical
excision that may reduce the recurrence rate (Fig 2) [19]. However, the literature
showed some reported cases that showed clinical improvement with medical treatment
only without surgical intervention [20–25]. There is no report of eumycetoma spontaneous
cure.
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Fig 2
Massive postoperative recurrence after adequate itraconazole treatment for one year.
Currently used drugs for eumycetoma
Various classes of antifungal drugs have been used in the treatment of eumycetoma
caused M. mycetomatis over the years, and that included the azoles, amphotericin B,
and terbinafine Table 1.
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Table 1
Reports on antifungals used for mycetoma treatment.
Drug
Study
No. of Patients
Dosage
Duration
Clinical Outcome
Principal Chronic Adverse Effect
Liposomal amphotericin B
Welsh et al. (2014) [10
4
3 mg/kg
6 weeks
No improvement
Nephrotoxicity
Sampaio FMS et al (2017) [27]
1
1 mg/kg
Not specified
No improvement
Terbinafine
N’Diaye et al (2006) [25]
10
1,000 mg /day
6–12 months
Responses ranged from cure to no improvement or even deterioration
Hepatotoxicity
Seck et al (2019) [29]
1
750 mg/day
8 months
Death
Ketoconazole
Venugopal et al (1993) [20]
4
400 mg/day
8–12 months
Good improvement in 3 patients, while one had only slight improvement
Life-threatening hepatotoxicity
Mahgoub et al (1984) [32]
13
100–400 mg/day
3–36 months
Responses ranged from cure to no improvement or even deterioration
Itraconazole
Fahal et al (2011) [34]
13
200–400 mg/day
12 months
Responses ranged from cure to massive recurrence
Hepatotoxicity
Voriconazole
Lacroix et al (2005) [22
1
400–600 mg/day
16 months
Cure
Hepatotoxicity
Loulergue et al (2006) [23]
1
400 mg/day
12 months
Good improvement
Posaconazole
Negroni et al (2005) [24]
2
800 mg/day
12 months
One patient had good improvement while the other showed no improvement
Hepatotoxicity
The toxicity and the need for hospitalization have greatly limited the use of amphotericin
B for treatment of eumycetoma [26]. Liposomal amphotericin B was used in four patients
at the Mycetoma Research Centre in Sudan (with a dose of 3 mg per kg) and one patient
in Brazil (with a dose of 1 mg per kg). However, the clinical response was not satisfactory,
and some of the patients experienced severe nephrotoxicity [10,27]. Intralesional
administration of amphotericin B was reported in a case of eumycetoma caused by Madurella
grisea in Brazil, and it resulted in a relatively good improvement [28]. However,
in eumycetoma caused by M. mycetomatis, the lesions are usually multilobulated; hence,
the even diffusion of the drug may not be possible. Furthermore, it is a painful procedure
and may disseminate the infection.
The use of terbinafine was reported in a study in Senegal where patients were treated
with 500 mg twice a day for 24 to 48 weeks that resulted in significant improvement
of 80% of the patients [25]. Terbinafine use was also reported on a 13-year-old Senegalese
boy with a dose of 750 mg per day. Nevertheless the boy passed away after 8 months
of treatment [29]. The limited use of terbinafine could be attributed at least to
its high cost and hepatotoxicity [30].
Generally, azoles remain the most commonly used class of antifungal drugs in the treatment
of eumycetoma. Before it was banned in 2013, due to life-threatening hepatotoxicity
[31], oral ketoconazole in a dose of 100 to 800 mg per day, was the treatment of choice
[20,32,33]. It was then replaced by itraconazole in a daily dose of 200 to 400 mg
per day [21,34]. Some newer azoles, such as voriconazole (400 to 600 mg per day) and
posaconazole (800 mg per day), have also been employed in the management of some eumycetoma
patients with good clinical outcomes [22–24]. However, their high cost compared to
itraconazole might have limited their use in poor developing countries where the disease
is endemic.
Itraconazole is considered as the most commonly used azole for eumycetoma treatment
[10]. However, itraconazole suffers from several inadequacies which include the following.
Suboptimal treatment outcomes and recurrence
The clinical response to itraconazole is often variable and is often associated with
recurrence even after extended treatment periods before and after surgery (Fig 3).
In one study, 13 patients were treated with itraconazole for 12 months in a dose of
400 mg per day for three months and then reduced to 200 mg per day for nine months;
only one patient showed complete cure, nine patients showed partial response, and
the rest three had stable disease. Later, one patient had a massive recurrence after
partial cure [34]. In another larger prospective study, only 321 of 1,242 (25.9%)
eumycetoma patients were cured [35]. Despite prolonged treatment with itraconazole
before and after surgery, postoperative recurrence is quite common. Recurrence was
reported in 276 of 1,013 patients (27.2%) treated by itraconazole accompanied by surgery
at the MRC in Sudan [36].
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Fig 3
Melanin in histopathology.
Prolonged treatment duration and adverse effects
Extended treatment duration with itraconazole was shown to be an important predictor
for attaining higher cure rates in eumycetoma patients [35]. Thus, eumycetoma patients
usually need to endure 6 months to 3 years of treatment with itraconazole [37]. This
in turn greatly affects patients’ adherence and compliance and results in high follow-up
dropout rates [35]. Such prolonged treatment periods also make patients more vulnerable
to serious adverse effects. Like other azoles, lengthy use of itraconazole affects
liver functions, ranging from transient elevations in serum transaminases to hepatoxicity
and liver failure [30].
Additionally, itraconazole has negative inotropic effects on the heart and has therefore
been associated with congestive heart failure [38–40]. Being an azole, itraconazole
is contraindicated in pregnancy since it is embryotoxic and teratogenic in animals
(Pregnancy Risk Category C) [41]. Moreover, pregnant women exposed to itraconazole
were shown to have an increased risk of early fetal loss [42].
Organism viability within the grains
Even though M. mycetomatis is highly susceptible to itraconazole in vitro [43,44],
grains containing viable fungi were isolated from patients who were on prolonged treatment
with itraconazole [34]. Hence, itraconazole seems to only limit the extent of the
infection instead of complete eradication of the M. mycetomatis’ tissue burden [45].
Drug pharmacokinetics
The pharmacokinetic profile of itraconazole is known to have considerable interpatient
variability while using the same dose of the drug [46]. This erratic variation could
largely be attributed to the fact that the absorption of itraconazole form the gastrointestinal
tract is greatly influenced by stomach acidity and concomitant food intake [47–50].
At best, the amount of itraconazole available for therapeutic activity represents
only 0.11% of the ingested dose. This could be attributed to the fact that the absolute
oral bioavailability of itraconazole is only 55% and, of that absorbed fraction, 99.8%
is bound to plasma proteins and thus considered unavailable for therapeutic effects
[50–52]. Consequently, this pharmacokinetic profile of itraconazole adds unnecessary
cost to the patients. Furthermore, due to high protein binding itraconazole can only
reach the cerebrospinal fluid in minimal amounts [50,52], this limits its therapeutic
effectiveness in cerebral eumycetoma infections.
Drug–drug interactions
Eumycetoma is a chronic medical condition and patients may develop several comorbidities
during the course of their infection. This will necessitate the coadministration of
drugs that might have undesirable pharmacokinetic interactions with itraconazole,
at the level of absorption, distribution, metabolism, or excretion [53–55]. These
interactions could result in decreased or increased plasma levels of itraconazole
or coadministered drugs, thus leading to reduced efficacy or increased toxicity, respectively.
For instance, administration of acid neutralising (e.g., aluminium hydroxide) or suppressing
(e.g. H2-antagonists as ranitidine or proton-pump inhibitors as omeprazole) drugs
lead to inadequate absorption of itraconazole [56–58]. Itraconazole is a potent inhibitor
and also a substrate of Cytochrome P450 3A4 (CYP3A4), which is responsible for the
metabolism of a broad range of drugs [59,60]. Consequently, itraconazole will increase
plasma concentrations of CYP3A4 substrates, while inducers and inhibitors of CYP3A4
will decrease or increase itraconazole plasma concentrations, respectively. Therefore,
levels of itraconazole and other coadministered drugs should be closely monitored
to avoid subclinical concentrations or undesired toxic effects of both drugs (Table
2).
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Table 2
Some drugs that could affect the metabolism of itraconazole or be affected by itraconazole
coadministration.
Drugs affecting itraconazole metabolism
Drugs which metabolism is inhibited by itraconazole
Drugs inhibiting Itraconazole metabolism
Antihistamines (e.g., astemizole, terfenadine)
HIV protease inhibitors (e.g., ritonavir, indinavir) *
Benzodiazepine sedatives (e.g., midazolam, diazepam, triazolam, alprazolam)
Macrolide antibiotics (e.g., erythromycin and clarithromycin)
Calcium channel blockers (e.g., amlodipine, nifedipine)
Drugs inducing itraconazole metabolism
HIV protease inhibitors (e.g., ritonavir, indinavir) *
Anticonvulsants (e.g., phenytoin, phenobarbital, carbamazepine)
HMG-CoA reductase inhibitors (e.g., lovastatin, atorvastatin)
Antimycobacterials (e.g., rifampin, isoniazid)
Oral hypoglycaemics (e.g., glimepiride, chlorpropamide, metformin).
Oral anticoagulants (e.g., Warfarin)
Immunosuppressants (e.g., Cyclosporine)
Anticancers (e.g., vincristine)
Digoxin
Cisapride
Methylprednisolone
Sildenafil citrate
Quinidine
* Concomitant use of itraconazole with protease inhibitors may result in a dual interaction
that leads to changes in plasma concentrations of both drugs.
Combination therapy
Most invasive fungal infections are difficult to treat with antifungal monotherapy.
Thus, combining antifungal drugs seems to be a promising approach to achieve synergistic
effects that could improve overall efficacy and decrease the duration of treatment,
toxicity, and possibly resistance [61].
Antifungal combination therapy can produce synergy via several mechanisms. One mechanism
could involve the inhibition of different stages of one biochemical pathway. Such
synergy could be seen in the combination of azoles and terbinafine, in which they
affect the integrity of the fungal cell membrane by targeting ergosterol biosynthesis
at various levels [62]. The use of such combinations has been reported for eumycetoma
caused by M. mycetomatis. In India, a patient was successfully treated using a combination
of itraconazole (400 mg per day) and terbinafine (250 mg per day) [63]. In another
case series, two patients were treated with a combination of voriconazole (400 to
700 mg per day) or posaconazole (800 mg per day) with terbinafine (dose not specified).
One patient did not respond to treatment, while the other showed very good clinical
improvement [64].
Synergy could also be achieved by combining azoles with flucytosine, in which azole
damage the fungal cell membrane, thus enhancing the penetration of flucytosine to
its target, where it inhibits the synthesis of both DNA and RNA [62,65]. The use of
posaconazole (800 mg per day) combined with flucytosine (80 mg per kg per day) was
also reported to produce good clinical improvement in eumycetoma patients [64,66].
The treatment of eumycetoma caused by M. mycetomatis is often complicated by the development
of bacterial coinfections, most commonly by Staphylococcus aureus [67]. Combining
antibacterial drugs such as an amoxicillin–clavulanic acid (2 g per day) with the
regular antifungal regimen helps in eradicating the bacterial coinfection and, hence,
improving the overall clinical outcome of the patients [68]. The use of such combinations
has been reported in the literature but without a clear rationale for their administration
because no bacterial coinfections were described. One eumycetoma patient showed good
clinical response upon treatment with a combination of intravenous trimethoprim–sulfamethoxazole
and liposomal amphotericin B (doses not specified) then a combination of oral trimethoprim–sulfamethoxazole
(320 mg per day) with posaconazole (800 mg per day) and ciprofloxacin (1 Gram per
day) [69]. Similarly, the combination of itraconazole with trimethoprim–sulfamethoxazole
(doses not specified) resulted in good improvement in two patients in Brazil. The
authors suggested that sulfamethoxazole–trimethoprim might have some activity against
the causative fungi [70].
Eumycetoma is usually associated with intense inflammatory reactions produced by the
host tissue [71], which are proposed to play an important role in the pathogenesis
of the disease [66]. Hence, combining antiinflammatory drugs with antifungal therapy
could help in improving the clinical outcomes of eumycetoma patients. Addition of
the nonsteroidal antiinflammatory drug, diclofenac (100 mg per day), to a combination
of posaconazole (800 mg per day) and flucytosine (80 mg per kg per day), resulted
in complete normalisation of the clinical picture within two months of a patient who
had refractory mycetoma for over 20 years [66]. In Brazil, combining oral prednisolone
with antifungals and sulfamethoxazole plus trimethoprim was also reported to enhance
the clinical improvement cure rates of patients without causing additional side effects
[72].
Possible barriers to effective treatment
In vitro, M. mycetomatis is susceptible to various classes of antifungals, yet the
clinical outcomes of these agents are unsatisfactory [44,73–76]. Many co-operating
factors might contribute to these poor clinical outcomes, such as:
Grains melanin
The black colour of M. mycetomatis grains is due to the fungi ability to produces
two types of melanin: pyo-melanin (soluble and secreted by the fungus) and dihydroxynaphthalene
(DHN)-melanin (solid, insoluble, and, usually, bound to the cell wall) Fig 4 [11].
The latter melanin was shown to reduce the in vitro efficacy of itraconazole and ketoconazole
by 16- and 32-folds, respectively [77]. This was explained by the fact that DHN-melanin
hinders the accessibility of these drugs to the fungal mycelia [77,78]. Cell-mediated
immunity plays a major adjunct role to drugs in the control and eradication of fungal
infections [79]. DHN-melanin was found to protect M. mycetomatis in vitro from the
killing effects of permanganate: one of the strongest known oxidants. Hence, inside
the host, this melanin may act as a scavenger for immune oxidants, such as nitric
oxide produced against the fungal invasion [77]. Interestingly, fungi have been shown
to increase the production of DHN-melanin when challenged with itraconazole, possibly
conferring additional protection against the drug [80].
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Fig 4
Massive thick capsule around the eumycetoma lesions.
The collagen
Following prolonged treatment with itraconazole or ketoconazole, M. mycetomatis grains
are usually found to be encapsulated with excessive collagen (Fig 5). This collagen
accumulation was found to be associated with elevated levels of active matrix metalloproteinases-9
(MMP-9) in eumycetoma patients [81] that probably disrupts the equilibrium of the
extracellular matrix (ECM) synthesis and degradation. Such dense collagen networks
around the fungal lesion might localize the infection, though it has also been suggested
that it might hinder drug accessibility and, hence, diminish the response to antifungal
treatment [81]. Such effects of collagen on penetration have been reported in macromolecules;
however, similar effects on micromolecules such as antifungal agents need further
investigation [82,83].
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Fig 5
Photomicroscopy showing M. mycetomatis grains well encapsulated with excessive collagen
following treatment with itraconazole (hematoxylin–eosin X 400).
The patients’ late presentation
A major problem with eumycetoma patients is the fact that they tend to present to
treatment at late stages with advanced disease (the median duration of the disease
at presentation is three years) [32]. This long disease duration seems to be an important
predictor of poor treatment outcomes [35]. This late presentation of eumycetoma patients
may be attributed to the substantial lack of health education and health facilities
in rural areas where eumycetoma is endemic. Furthermore, the high coast and far away
access to treatment combined with the patients’ low socioeconomic status led them
to first seek other treatment alternatives, such as herbal and traditional medicine.
Approximately 42.4% of eumycetoma patients have used herbal medicine during the course
of their disease [84]. Herbs such as Moringa oleifera, Acacia nilotica, Citrullus
colocynthis, and Cuminum cyminum were commonly used either alone or in combination
with other herbs [84]. Some patients also seek traditional and religious healing techniques
such as cautery, charms, amulets, hijabs, erasure (mihaya), and incantations (ruqia)
(Fig 6) [85]. These alternative treatments are usually not only ineffective in treating
eumycetoma but also lead to serious complications such as skin burns, necrosis, and,
most importantly, secondary bacterial infections [84].
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Fig 6
The use of traditional medicine for mycetoma.
Recommendation for improving currently available treatment
As has been stated, treatment of eumycetoma suffers from several shortcomings, most
importantly the limited treatment alternatives, which are associated with low cure
rates and great variability in response among patients. As have been mentioned previously,
combining antifungal drugs for the treatment of eumycetoma caused by M. mycetomatis
have shown some promising outcomes. However, these outcomes are limited to only a
few case reports [63,64,66]. That is why there is an urgent need for proper and controlled
clinical studies in larger numbers of patients to determine the most effective combination
of drugs, their doses, and duration of treatment. Furthermore, the outcomes of these
case reports do not coincide with in vitro and in vivo findings (using M. mycetomatis-infected
Galleria mellonella larvae), in which drug combinations did not result in synergy
nor improved the therapeutic response [86,87]. Developing a three-dimensional (organoid)
culture system for M. mycetomatis might aid in obtaining a better reflection of the
host–pathogen complex biological interactions [88] and, hence, a more accurate prediction
of the fungi’s response to drugs and their combinations [89].
The variable and unsatisfactory clinical response of eumycetoma patients to itraconazole
could partially be attributed to its poor pharmacokinetic profile. Maintaining effective
and safe serum levels of itraconazole in patients could be achieved via therapeutic
drug monitoring (TDM) techniques such as high-performance liquid chromatography (HPLC)
and mass spectrometry (MS) [90]. Furthermore, enhancing the oral bioavailability of
itraconazole could be a good approach to enhance its therapeutic efficacy, while reducing
treatment cost. Many pharmaceutical technologies have been developed over the years
to enhance the oral bioavailability of itraconazole. For example, an oral solution
of itraconazole was developed via incorporating it with a cyclodextrin vehicle, which
resulted in a 37% higher oral bioavailability compared to itraconazole capsule in
healthy volunteers [91,92]. Furthermore, the absorption of itraconazole from this
oral solution is enhanced when taken on an empty stomach [91]. Hence, using such formulations
in the management of eumycetoma might improve the clinical outcome of the disease.
As have been mentioned previously, the late presentation of eumycetoma patients is
a major hurdle in their treatment. Thus, implementing vigorous health education programs
in mycetoma endemic areas could be a possible solution. These educational programs
should also embrace the traditional healers as they are greatly trusted by the locals
and could help in detecting early cases. Once enrolled in treatment, patients should
be counselled on the potential drug–drug and drug–food interactions of itraconazole,
so as to maximize the effectiveness of the drug and minimise its potentially toxic
effects.
Eumycetoma results in serious disfigurement, scarring, and disability. Hence, patients
are often stigmatized in their communities. This could lead to patients being reluctant
to seek medical treatment once they notice their disease. Therefore, providing psychological
support and occupational rehabilitation for these patients could improve their adherence
to treatment and hence improve their treatment outcome.
Drug discovery for eumycetoma
As mentioned in the previous parts of the Review, the success rate of the currently
available treatment options for eumycetoma caused by M. mycetomatis is minimal. Accordingly,
there is a desperate need for finding new medicines to address the unmet clinical
need in the field of eumycetoma management.
Drug discovery for eumycetoma can take place by several means. Herein, two main ways
will be discussed. Firstly, the drug repurposing approach and secondly the de novo
drug discovery. In this issue, the term “de novo drug discovery” represents the discovery
of novel treatments through the regular drug discovery pipeline, which involves the
screening of chemical compounds, followed by in vitro, in vivo testing then preclinical
and clinical evaluation [93]. On the other hand, drug repurposing refers to the use
of approved medication for indications other than the one that it was originally developed
for [94]. Thus, drug repurposing could aid in finding novel medicines, while dramatically
cutting down expenses and shortening the drug discovery process by relying on existing
safety and pharmacokinetic profiles of drugs that are already in the market [94,95].
Drug repurposing for eumycetoma
Drug repurposing became an attractive approach for finding new treatments for diseases
like eumycetoma because these diseases occur primarily and almost solely in poor communities.
Hence, these diseases do not represent an attractive investment for pharmaceutical
companies, as their profits are not considered satisfactory enough to compensate for
the cost of the de novo drug discovery [96].
Among the examples of drug repurposing for eumycetoma, treatment is fosravuconazole.
The starting point for the application of fosravuconazole for treating eumycetoma
was ravuconazole. It is a newly developed broad-spectrum triazole that was initially
developed for the treatment of Chagas disease. In vitro studies showed that ravuconazole
is active against Madurella mycetomatis [74]. Nevertheless, ravuconazole is too expensive
to be applied directly in the treatment of eumycetoma, a disease that is almost restricted
to underprivileged communities. Fortunately, Eisai, a Japanese pharmaceutical company,
developed a more affordable prodrug of ravuconazole called fosravuconazole that is
presently being clinically assessed in the first double-blind clinical trial on eumycetoma
patients at the MRC in Sudan [97]. This trial hopes to deliver effective and affordable
treatment for eumycetoma.
The de novo drug discovery
The chief drawback of the de novo drug discovery is the fact that it is a long, time-consuming,
and financially demanding journey [98]. Nevertheless, there are still some initiatives
such as the Drugs for Neglected Diseases initiative (DNDi) that support the discovery
of treatments for neglected diseases, such as eumycetoma, through this path [99].
Among the DNDi moves towards finding new efficacious medications for eumycetoma was
to provide chemical entities for screening against M. mycetomatis. In one of the studies,
the in vitro and in vivo screening of more than 800 different compounds resulted in
the identification of several new hits that could potentially be developed into effective
drugs for eumycetoma caused by M. mycetomatis [100]. These previous findings were
the starting point of the Mycetoma Open Source project (MycetOS) in 2018 [101], which
focuses on discovering novel treatments for eumycetoma through an Open Pharma approach
[102]. Through an open-access database that is publicly driven, the project aims at
the discovery of new drugs and the optimization of available leads for management
of eumycetoma caused by M. mycetomatis. Thus, MycetOS does not belong to any specific
person or organization. It, rather, belongs to everyone who is willing to participate.