Combining two antifungal agents does not enhance survival of <i>Galleria mellonella</i> larvae infected with <i>Madurella mycetomatis</i>

Eadie, Kimberly; Parel, Florianne; Poppel, Marilyn Helvert-van; Fahal, Ahmed H.; Sande, Wendy W. J. van de

doi:10.1111/tmi.12871

Cited by 15 publications

(10 citation statements)

References 34 publications

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“…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].…”

Section: Recommendation For Improving Currently Available Treatmentmentioning

confidence: 64%

“…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 .…”

Section: Currently Used Drugs For Eumycetomamentioning

confidence: 99%

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Madurella mycetomatis causing eumycetoma medical treatment: The challenges and prospects

et al. 2020

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Section: Recommendation For Improving Currently Available Treatmentmentioning

confidence: 64%

Section: Currently Used Drugs For Eumycetomamentioning

confidence: 99%

Madurella mycetomatis causing eumycetoma medical treatment: The challenges and prospects

et al. 2020

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“…None of the compounds except MMV688943 (difenconazole) had a significant impact on melanization rate. As Eadie has described, compounds may influence the make-up of grains and their cement material, potentially increasing or decreasing the accessibility of M. mycetomatis to the larval immune system [39].…”

Section: Discussionmentioning

confidence: 99%

Addressing the Most Neglected Diseases through an Open Research Model: the Discovery of Fenarimols as Novel Drug Candidates for Eumycetoma

Lim

Melse

Konings

et al. 2018

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Eumycetoma is a chronic infectious disease characterized by a large subcutaneous mass, often caused by the fungus Madurella mycetomatis. A combination of surgery and prolonged medication is needed to treat this infection with a success rate of only 30%. There is, therefore, an urgent need to find more effective drugs for the treatment of this disease. In this study, we screened 800 diverse drug-like molecules and identified 215 molecules that were active in vitro. Minimal inhibitory concentrations were determined for the 13 most active compounds. One of the most potent compounds, a fenarimol analogue for which a large analogue library is available, led to the screening of an additional 35 compounds for their in vitro activity against M. mycetomatis hyphae, rendering four further hit compounds. To assess the in vivo potency of these hit compounds, a Galleria mellonella larvae model infected with M. mycetomatis was used. Several of the compounds identified in vitro demonstrated promising efficacy in vivo in terms of prolonged larval survival and/or reduced fungal burden. The results presented in this paper are the starting point of an Open Source Mycetoma (MycetOS) approach in which members of the global scientific community are invited to participate and contribute as equal partners. We hope that this initiative, coupled with the promising new hits we have reported, will lead to progress in drug discovery for this most neglected of neglected tropical diseases.Author summaryMycetoma is a poverty-associated disease that was recently recognised as a neglected tropical disease by the World Health Organisation (WHO). This disease can be caused by either bacteria (actinomycetoma) or fungi (eumycetoma). The most common causative agent of mycetoma is the fungus Madurella mycetomatis. Actinomycetoma can be easily treated, but for eumycetoma, the current and only antifungal drug used is only able to successfully treat 30% of patients. Treatment often involves prolonged medication use and amputation of the affected area. This disease is disfiguring and is a social stigma for patients in endemic countries. To improve treatment for patients, we have looked at over 800 diverse drug-like molecules and compounds in hope to develop new drugs in this study. We have identified 215 compounds with activity against M. mycetomatis in vitro and several in vivo with our Galleria mellonella larvae model. We have chosen an open source approach with this study and placed our findings in an online database and made it available to the public. We invite the global scientific community to participate in our study and contribute as equal partners as long as an open source approach is held in hopes to fast track and boost drug discovery for Eumycetoma.

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“…[32,33,[45][46][47][48][49][50][51], Aspergillus spp. [13,29,35,[52][53][54][55][56][57][58][59][60][61], Mucorales [62][63][64], Madurella mycetomatis [65][66][67], and other fungal agents [68][69][70]. The contribution of G. mellonella to the evaluation of antifungal drugs will be detailed in the following paragraphs.…”

Section: Evaluation Of Antifungal Efficacy In Galleria Mellonellamentioning

confidence: 99%

“…In contrast, azoles did not improve survival. Antifungal combinations were also tested in the same model [65]. Combination of itraconazole with terbinafine was not beneficial, while combination of amphotericin B with either itraconazole or terbinafine decreased survival compared to amphotericin B alone and was therefore antagonistic.…”

Section: Madurella Mycetomatismentioning

confidence: 99%

Galleria mellonella for the Evaluation of Antifungal Efficacy against Medically Important Fungi, a Narrative Review

et al. 2020

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The treatment of invasive fungal infections remains challenging and the emergence of new fungal pathogens as well as the development of resistance to the main antifungal drugs highlight the need for novel therapeutic strategies. Although in vitro antifungal susceptibility testing has come of age, the proper evaluation of therapeutic efficacy of current or new antifungals is dependent on the use of animal models. Mammalian models, particularly using rodents, are the cornerstone for evaluation of antifungal efficacy, but are limited by increased costs and ethical considerations. To circumvent these limitations, alternative invertebrate models, such as Galleria mellonella, have been developed. Larvae of G. mellonella have been widely used for testing virulence of fungi and more recently have proven useful for evaluation of antifungal efficacy. This model is suitable for infection by different fungal pathogens including yeasts (Candida, Cryptococcus, Trichosporon) and filamentous fungi (Aspergillus, Mucorales). Antifungal efficacy may be easily estimated by fungal burden or mortality rate in infected and treated larvae. The aim of the present review is to summarize the actual data about the use of G. mellonella for testing the in vivo efficacy of licensed antifungal drugs, new drugs, and combination therapies.

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Combining two antifungal agents does not enhance survival of Galleria mellonella larvae infected with Madurella mycetomatis

Cited by 15 publications

References 34 publications

Madurella mycetomatis causing eumycetoma medical treatment: The challenges and prospects

Madurella mycetomatis causing eumycetoma medical treatment: The challenges and prospects

Addressing the Most Neglected Diseases through an Open Research Model: the Discovery of Fenarimols as Novel Drug Candidates for Eumycetoma

Galleria mellonella for the Evaluation of Antifungal Efficacy against Medically Important Fungi, a Narrative Review

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