New facets of antifungal therapy

Chang, Yajie; Yu, Shu-Han; Heitman, Joseph; Wellington, Melanie; Chen, Ying-Lien

doi:10.1080/21505594.2016.1257457

Cited by 142 publications

(102 citation statements)

References 124 publications

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“…Several authors have demonstrated the beneficial interactions between different antifungal agents 11,24‐26 . Double and triple associations using clioquinol showed synergistic effect in the present study, and this complex interaction can be explained by the fact that each of the three drugs has simultaneous effect on different targets.…”

Section: Discussionsupporting

confidence: 64%

In vitro antidermatophytic synergism of double and triple combination of clioquinol with ciclopirox and terbinafine

Costa

Pippi

Kaminski

et al. 2020

Mycoses

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Summary Background Dermatophytoses are the most frequent fungal infections worldwide and there have been described clinical resistance to the commonly used antifungals. Clioquinol is an antimicrobial that had the oral formulations withdrawn from the market in the 70s due to the report of neurotoxicity and recently has been considered as an effective alternative for the treatment of dermatophytosis. Objectives To evaluate the effect of the double and triple association between clioquinol with terbinafine and ciclopirox on clinical isolates of dermatophytes. The cytotoxicity of these associations on human leukocytes was also verified. Methods Checkerboard method was used to evaluate the interaction between antifungal agents. Time‐kill assay was used to verify fungicidal action and evaluate the combination with greater effect for TRU47 isolate. Cell viability was assessed by loss of integrity of the leukocyte membrane in order to verify the toxicity. Results Synergistic interaction was observed in 42% of isolates when terbinafine was associated with clioquinol and in 50% of isolates when ciclopirox was associated with clioquinol. The triple association resulted in synergistic interaction for 75% of the isolates. Clioquinol + terbinafine and triple combination were more effective for TRU47 isolate, and the combinations exhibited a time‐dependent fungicidal effect. Furthermore, the results of cell viability demonstrated that clioquinol and terbinafine combination is not cytotoxic to human leukocytes. Conclusions Clioquinol in combination with antifungals in the treatment of dermatophytosis can be a therapeutic strategy to overcome problems related to resistance, action spectrum and toxicity of the antifungal drugs used in the clinic.

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Section: Discussionsupporting

confidence: 64%

In vitro antidermatophytic synergism of double and triple combination of clioquinol with ciclopirox and terbinafine

Costa

Pippi

Kaminski

et al. 2020

Mycoses

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“…1·2 billion individuals worldwide with at least 1·5 million deaths each year (Campoy and Adrio ; Chang et al . ). Furthermore, the widespread use of antifungal drugs are bringing serious consequences for antifungal therapy, due to the emergence of resistant strains and therefore leading to treatment failures (Pfaller ; Tobudic et al .…”

Section: Introductionmentioning

confidence: 97%

Antifungals discovery: an insight into new strategies to combat antifungal resistance

Fuentefría

Pippi

Lana

et al. 2018

Letters in Applied Microbiology

149

109

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Significance and Impact of the Study: The failure to respond to antifungal therapy is complex and is associated with microbiological resistance and increased expression of virulence in fungal pathogens. Thus, this review offers an overview of current challenges in the treatment of fungal infections associated with increased antifungal drug resistance and the formation of biofilms in these opportunistic pathogens. Furthermore, the most recent and potential strategies to combat fungal pathogens are explored here, focusing on new agents as well as innovative approaches, such as combination therapy between antifungal drugs or with natural compounds. AbstractUndeniably, new antifungal treatments are necessary against pathogenic fungi. Fungal infections have significantly increased in recent decades, being highlighted as important causes of morbidity and mortality, particularly in immunocompromised patients. Five main antifungal classes are used: (i) azoles, (ii) echinocandins, (iii) polyenes, (iv) allylamines and (v) pyrimidine analogues. Moreover, the treatment of mycoses has several limitations, such as undesirable side effects, narrow activity spectrum, a small number of targets and fungal resistance, which are still of major concern in clinical practice. The discovery of new antifungals is mostly achieved by the screening of natural or synthetic/semisynthetic chemical compounds. The most recent discoveries in drug resistance mechanism and their avoidance were explored in a review, focusing on different antifungal targets, as well as new agents or strategies, such as combination therapy, that could improve antifungal therapy.

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“…Combination antifungal therapy is of increasing interest as a means to modulate antifungal resistance and/or improve antifungal efficacy (24). To assess the interactions between currently used antifungal drugs and MEF-derivatives, we performed checkerboard microdilution assays and analyzed data using the fractional inhibitory concentration index (FICI).…”

Section: Resultsmentioning

confidence: 99%

Derivatives of the antimalarial drug mefloquine are broad spectrum antifungal molecules with activity against drug-resistant clinical isolates

Montoya

Beattie

Alden

et al. 2019

Preprint

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20 21 22 23The antifungal pharmacopeia is critically small, particularly in light of the recent 24 emergence of multi-drug-resistant pathogens such as Candida auris. Herein, we report 25 that derivatives of the anti-malarial drug mefloquine have broad spectrum antifungal 26 activity against pathogenic yeasts and molds. In addition, the mefloquine derivatives have 27 activity against clinical isolates that are resistant to one or more of the three classes of 28 drugs currently used to treat invasive fungal infections, indicating that they have a novel 29 mechanism of action. Importantly, the in vitro toxicity profiles using human cell lines 30 indicate that the mefloquine derivatives are very similar to the parent mefloquine despite 31 being up to 64-fold more active against fungal cells. In addition to direct antifungal activity, 32 sub-inhibitory concentrations of the mefloquine derivatives inhibit the expression of 33 virulence traits including filamentation in C. albicans and capsule formation/melanization 34 in C. neoformans. Mode/mechanism of action experiments indicate that the mefloquine 35 derivatives interfere with both mitochondrial and vacuolar function as part of a multi-target 36 mechanism of action. The broad-spectrum scope of activity, blood-brain-barrier 37 penetration, and large number of previously synthesized analogs available combine to 38 support the further optimization and development of the antifungal activity of this general 39 class of drug-like molecules. 40 41 was the availability of structural analogs of MEF through the NCI experimental 88 therapeutics program. 89 MEF has also been studied as a repurposing candidate against other human 90 parasites including schistosomiasis, toxoplasmosis, and echinococcosis (11-17). MEF 91 has also shown antibacterial activity against Streptococcus pneumoniae and 92 Mycobacterium tuberculosis (18, 19). Additionally, repurposing efforts have found 93 antiviral activity against Ebola, Dengue, and Zika virus (20, 21). Most importantly a small 94 set of MEF-derivatives were shown to have activity against Cryptococcus neoformans 95 and Candida albicans (22). Despite these promising findings, no additional 96 characterization of the antifungal activity of the MEF-derivatives has been reported. Here, 97 we show that MEF-derivatives have broad spectrum antifungal activity against both 98 susceptible and drug-resistant fungi; show synergy with existing antifungal drugs; 99 modulate the expression of virulence traits in both C. albicans and C. neoformans; and 100interfere with the functions and interactions of mitochondria and vacuoles in fungi. 101 RESULTS 102Mefloquine derivatives have in vitro antifungal activity against a variety of human 103 fungal pathogens. 104 To explore the antifungal activity of the MEF scaffold, we first tested MEF against 105 a set of reference strains of pathogenic fungi including C. albicans, C. glabrata, C. auris, 106 C. neoformans, and A. fumigatus as well as the model yeast S. cerevisiae (Table 1). 107 Consistent with...

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New facets of antifungal therapy

Cited by 142 publications

References 124 publications

In vitro antidermatophytic synergism of double and triple combination of clioquinol with ciclopirox and terbinafine

In vitro antidermatophytic synergism of double and triple combination of clioquinol with ciclopirox and terbinafine

Antifungals discovery: an insight into new strategies to combat antifungal resistance

Derivatives of the antimalarial drug mefloquine are broad spectrum antifungal molecules with activity against drug-resistant clinical isolates

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