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International Journal of Molecular... Jun 2024Eumycetoma is a neglected tropical disease (NTD) characterized by subcutaneous lesions and the formation of grains. Attempts to treat eumycetoma involve a combination of...
OBJECTIVES
Eumycetoma is a neglected tropical disease (NTD) characterized by subcutaneous lesions and the formation of grains. Attempts to treat eumycetoma involve a combination of antifungal treatment and surgery, although the outcome is frequently disappointing. Therefore, there is a need to identify novel antifungal drugs to treat eumycetoma. In this respect, Medicines for Malaria Venture (MMV) has assembled libraries of compounds for researchers to use in drug discovery research against NTD. Therefore, we screened two MMVOpen compound libraries to identify novel leads for eumycetoma.
METHODS
A total of 400 compounds from the COVID Box and the Global Health Priority Box were screened in vitro at 100 µM and 25 µM against the most common causative agents of eumycetoma, namely and and the resulting IC and MIC values were obtained. Compounds with an IC < 8 µM were identified for possible in vivo efficacy studies using an grain model in larvae.
RESULTS
Out of the 400 compounds, 22 were able to inhibit both and growth at 100 µM and 25 µM, with compounds MMV1593278, MMV020335, and MMV1804559 being selected for in vivo testing. Of these three, only the pyrazolopyrimidine derivative MMV1804559 was able to prolong the survival of -infected larvae. Furthermore, the grains in MMV1804559-treated larvae were significantly smaller compared to the PBS-treated group.
CONCLUSION
MMV1804559 shows promising in vitro and in vivo activity against .
Topics: Madurella; Mycetoma; Antifungal Agents; Animals; Microbial Sensitivity Tests; Larva; Humans
PubMed: 38892422
DOI: 10.3390/ijms25116227 -
Molecules (Basel, Switzerland) Apr 2024In the search for new bioactive agents against the infectious pathogen responsible for the neglected tropical disease (NTD) mycetoma, we tested a collection of 27...
In the search for new bioactive agents against the infectious pathogen responsible for the neglected tropical disease (NTD) mycetoma, we tested a collection of 27 essential oils (EOs) in vitro against , the primary pathogen responsible for the fungal form of mycetoma, termed eumycetoma. Among this series, the EO of (Santalaceae), i.e., East Indian sandalwood oil, stood out prominently with the most potent inhibition in vitro. We, therefore, directed our research toward 15 EOs of species of different geographical origins, along with two samples of EOs from other plant species often commercialized as "sandalwood oils". Most of these EOs displayed similar strong activity against in vitro. All tested oils were thoroughly analyzed by GC-QTOF MS and most of their constituents were identified. Separation of the sandalwood oil into the fractions of sesquiterpene hydrocarbons and alcohols showed that its activity is associated with the sesquiterpene alcohols. The major constituents, the sesquiterpene alcohols ()-α- and ()-β-santalol were isolated from the oil by column chromatography on AgNO-coated silica. They were tested as isolated compounds against the fungus, and ()-α-santalol was about two times more active than the β-isomer.
Topics: Madurella; Plant Oils; Oils, Volatile; Mycetoma; Santalum; Sesquiterpenes; Antifungal Agents; Microbial Sensitivity Tests
PubMed: 38675665
DOI: 10.3390/molecules29081846 -
Plants (Basel, Switzerland) May 2024The synthesis of betalain using microorganisms is an innovative developmental technology, and the excavation of microorganisms closely related to betalain can provide...
The synthesis of betalain using microorganisms is an innovative developmental technology, and the excavation of microorganisms closely related to betalain can provide certain theoretical and technical support to this technology. In this study, the characteristics of soil microbial community structures and their functions in the rhizospheres of white-fleshed dragon fruit () and red-fleshed dragon fruit () were analyzed. The results show that the soil bacterial and fungal compositions in the rhizospheres were shaped differently between and . Bacterial genera such as and were the unique dominant soil bacterial genera in the rhizospheres of , whereas was the unique dominant soil bacterial genus in the rhizospheres of . Additionally, was the unique dominant soil fungal genus in the rhizospheres of , whereas and were the unique dominant soil fungal genera in the rhizospheres of . Moreover, , , , , , , , and were significantly enriched in the rhizospheres of , whereas , , , , and were significantly enriched in the rhizospheres of . Furthermore, the relative abundances of Ascomycota and were significantly higher in the rhizospheres of than in those of .
PubMed: 38794417
DOI: 10.3390/plants13101346 -
Medical Mycology Jun 2024The World Health Organization, in response to the growing burden of fungal disease, established a process to develop a fungal priority pathogens list. This systematic...
The World Health Organization, in response to the growing burden of fungal disease, established a process to develop a fungal priority pathogens list. This systematic review aimed to evaluate the epidemiology and impact of eumycetoma. PubMed and Web of Science were searched to identify studies published between 1 January 2011 and 19 February 2021. Studies reporting on mortality, inpatient care, complications and sequelae, antifungal susceptibility, risk factors, preventability, annual incidence, global distribution, and emergence during the study time frames were selected. Overall, 14 studies were eligible for inclusion. Morbidity was frequent with moderate to severe impairment of quality of life in 60.3%, amputation in up to 38.5%, and recurrent or long-term disease in 31.8%-73.5% of patients. Potential risk factors included male gender (56.6%-79.6%), younger age (11-30 years; 64%), and farming occupation (62.1%-69.7%). Mycetoma was predominantly reported in Sudan, particularly in central Sudan (37%-76.6% of cases). An annual incidence of 0.1/100 000 persons and 0.32/100 000 persons/decade was reported in the Philippines and Uganda, respectively. In Uganda, a decline in incidence from 3.37 to 0.32/100 000 persons between two consecutive 10-year periods (2000-2009 and 2010-2019) was detected. A community-based, multi-pronged prevention programme was associated with a reduction in amputation rates from 62.8% to 11.9%. With the pre-specified criteria, no studies of antifungal drug susceptibility, mortality, and hospital lengths of stay were identified. Future research should include larger cohort studies, greater drug susceptibility testing, and global surveillance to develop evidence-based treatment guidelines and to determine more accurately the incidence and trends over time.
Topics: Humans; Mycetoma; Incidence; Antifungal Agents; World Health Organization; Risk Factors; Male; Female; Quality of Life
PubMed: 38935904
DOI: 10.1093/mmy/myae044 -
PLoS Neglected Tropical Diseases Apr 2024Madurella mycetomatis is the main cause of mycetoma, a chronic granulomatous infection for which currently no adequate therapy is available. To improve therapy, more...
Madurella mycetomatis is the main cause of mycetoma, a chronic granulomatous infection for which currently no adequate therapy is available. To improve therapy, more knowledge on a molecular level is required to understand how M. mycetomatis is able to cause this disease. However, the genetic toolbox for M. mycetomatis is limited. To date, no method is available to genetically modify M. mycetomatis. In this paper, a protoplast-mediated transformation protocol was successfully developed for this fungal species, using hygromycin as a selection marker. Furthermore, using this method, a cytoplasmic-GFP-expressing M. mycetomatis strain was created. The reported methodology will be invaluable to explore the pathogenicity of M. mycetomatis and to develop reporter strains which can be useful in drug discovery as well as in genetic studies.
Topics: Hygromycin B; Madurella; Protoplasts; Transformation, Genetic; Drug Resistance, Fungal; Mycetoma; Cinnamates
PubMed: 38578808
DOI: 10.1371/journal.pntd.0012092 -
Antimicrobial Agents and Chemotherapy May 2024Mycetoma is a devastating neglected tropical infection of the subcutaneous tissues. It is caused by fungal and bacterial pathogens recognized as eumycetoma and...
Mycetoma is a devastating neglected tropical infection of the subcutaneous tissues. It is caused by fungal and bacterial pathogens recognized as eumycetoma and actinomycetoma, respectively. Mycetoma treatment involves diagnosing the causative microorganism as a prerequisite to prescribing a proper medication. Current therapy of fungal eumycetoma causative agents, such as , consists of long-term antifungal medication with itraconazole followed by surgery, yet with usually unsatisfactory clinical outcomes. Actinomycetoma, on the contrary, usually responds to treatment with co-trimoxazole and amikacin. Therefore, there is a pressing need to discover novel broad-spectrum antimicrobial agents to circumvent the time-consuming and costly diagnosis. Using the resazurin assay, a series of 23 naphthylisoquinoline (NIQ) alkaloids and related naphthoquinones were subjected to screening against two fungal strains of and three bacterial strains of and . Seven NIQs, mostly dimers, showed promising activities against at least one strain of the mycetoma-causative pathogens, while the naphthoquinones did not show any activity. A synthetic NIQ dimer, 8,8'''-,-dimethylmichellamine A (), inhibited all tested fungal and bacterial strains (IC = 2.81-12.07 µg/mL). One of the dimeric NIQs, michellamine B (), inhibited a strain of and significantly enhanced the survival rate of larvae infected with at concentrations of 1 and 4 µg/mL, without being toxic to the uninfected larvae. As a result, broad-spectrum dimeric NIQs like and with antimicrobial activity are considered hit compounds that could be worth further optimization to develop novel lead antimycetomal agents.
Topics: Mycetoma; Antifungal Agents; Animals; Alkaloids; Microbial Sensitivity Tests; Madurella; Isoquinolines; Actinomadura; Naphthoquinones; Larva; Moths
PubMed: 38602413
DOI: 10.1128/aac.01612-23 -
Mycoses Jan 2024(1,3)-β-D-glucan is a panfungal biomarker secreted by many fungi, including Madurella mycetomatis, the main causative agent of eumycetoma. Previously we demonstrated...
INTRODUCTION
(1,3)-β-D-glucan is a panfungal biomarker secreted by many fungi, including Madurella mycetomatis, the main causative agent of eumycetoma. Previously we demonstrated that (1,3)-β-D-glucan was present in serum of patients with eumycetoma. However, the use of (1,3)-β-D-glucan to monitor treatment responses in patients with eumycetoma has not been evaluated.
MATERIALS AND METHODS
In this study, we measured (1,3)-β-D-glucan concentrations in serum with the WAKO (1,3)-β-D-glucan assay in 104 patients with eumycetoma treated with either 400 mg itraconazole daily, or 200 mg or 300 mg fosravuconazole weekly. Serial serum (1,3)-β-D-glucan concentrations were measured at seven different timepoints. Any correlation between initial and final (1,3)-β-D-glucan concentrations and clinical outcome was evaluated.
RESULTS
The concentration of (1,3)-β-D-glucan was obtained in a total of 654 serum samples. Before treatment, the average (1,3)-β-D-glucan concentration was 22.86 pg/mL. During the first 6 months of treatment, this concentration remained stable. (1,3)-β-D-glucan concentrations significantly dropped after surgery to 8.56 pg/mL. After treatment was stopped, there was clinical evidence of recurrence in 18 patients. Seven of these 18 patients had a (1,3)-β-D-glucan concentration above the 5.5 pg/mL cut-off value for positivity, while in the remaining 11 patients, (1,3)-β-D-glucan concentrations were below the cut-off value. This resulted in a sensitivity of 38.9% and specificity of 75.0%. A correlation between lesion size and (1,3)-β-D-glucan concentration was noted.
CONCLUSION
Although in general (1,3)-β-D-glucan concentrations can be measured in the serum of patients with eumycetoma during treatment, a sharp decrease in β-glucan concentration was only noted after surgery and not during or after antimicrobial treatment. (1,3)-β-D-glucan concentrations were not predictive for recurrence and seem to have no value in determining treatment response to azoles in patients with eumycetoma.
Topics: Humans; Madurella; Glucans; Azoles; Mycetoma; Proteoglycans
PubMed: 37872649
DOI: 10.1111/myc.13664 -
Indian Journal of Medical Microbiology 2024Eumycetoma caused by Madurella fahalii, a drug-resistant fungus, has never been reported in India. Here, we describe a fatal case of eumycetoma with spinal involvement...
Eumycetoma caused by Madurella fahalii, a drug-resistant fungus, has never been reported in India. Here, we describe a fatal case of eumycetoma with spinal involvement due to M. fahalii for the first time in India.
Topics: Humans; India; Mycetoma; Madurella; Male; Fatal Outcome; Spine; Antifungal Agents
PubMed: 38158183
DOI: 10.1016/j.ijmmb.2023.100523