A complex game of hide and seek: the search for new antifungals

Ngo, Huy; Garneau‐Tsodikova, Sylvie; Green, Keith D.

doi:10.1039/c6md00222f

Cited by 52 publications

(38 citation statements)

References 193 publications

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“…Although the commercially available antifungal agents to date have targets that are restricted to the plasma membrane and the cell wall (Odds et al, 2003; Sundriyal et al, 2006; Ngo et al, 2016), a certain diversity of targets has been discovered. To develop new therapies, recent studies have focused on the inhibition of fungal virulence factors.…”

Section: Antifungal Mechanism Of Action: Old and New Targets Of Antifmentioning

confidence: 99%

“…This inhibition leads to accumulation of squalene and the absence of other sterol derivatives. Allylamines are highly effective against dermatophytes because they have been shown to accumulate more in the skin and nail beds relative to the blood, possibly due to their lipophilicity (Ngo et al, 2016). …”

Section: Antifungal Mechanism Of Action: Old and New Targets Of Antifmentioning

confidence: 99%

“…However, the current increase in incidence of fungal infections has led to aggressive research on new antifungal agents as evidenced by the rise in the number of publications since the 1960s (Maertens, 2004; Ngo et al, 2016). Another reason for the slow development of antifungal agents is the fact that fungi are eukaryotic, with a close evolutionary relationship with human hosts, which complicates the search for antifungal targets.…”

Section: Introductionmentioning

confidence: 99%

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Antifungal Therapy: New Advances in the Understanding and Treatment of Mycosis

et al. 2017

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The high rates of morbidity and mortality caused by fungal infections are associated with the current limited antifungal arsenal and the high toxicity of the compounds. Additionally, identifying novel drug targets is challenging because there are many similarities between fungal and human cells. The most common antifungal targets include fungal RNA synthesis and cell wall and membrane components, though new antifungal targets are being investigated. Nonetheless, fungi have developed resistance mechanisms, such as overexpression of eﬄux pump proteins and biofilm formation, emphasizing the importance of understanding these mechanisms. To address these problems, different approaches to preventing and treating fungal diseases are described in this review, with a focus on the resistance mechanisms of fungi, with the goal of developing efficient strategies to overcoming and preventing resistance as well as new advances in antifungal therapy. Due to the limited antifungal arsenal, researchers have sought to improve treatment via different approaches, and the synergistic effect obtained by the combination of antifungals contributes to reducing toxicity and could be an alternative for treatment. Another important issue is the development of new formulations for antifungal agents, and interest in nanoparticles as new types of carriers of antifungal drugs has increased. In addition, modifications to the chemical structures of traditional antifungals have improved their activity and pharmacokinetic parameters. Moreover, a different approach to preventing and treating fungal diseases is immunotherapy, which involves different mechanisms, such as vaccines, activation of the immune response and inducing the production of host antimicrobial molecules. Finally, the use of a mini-host has been encouraging for in vivo testing because these animal models demonstrate a good correlation with the mammalian model; they also increase the speediness of as well as facilitate the preliminary testing of new antifungal agents. In general, many years are required from discovery of a new antifungal to clinical use. However, the development of new antifungal strategies will reduce the therapeutic time and/or increase the quality of life of patients.

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Section: Antifungal Mechanism Of Action: Old and New Targets Of Antifmentioning

confidence: 99%

Section: Antifungal Mechanism Of Action: Old and New Targets Of Antifmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Antifungal Therapy: New Advances in the Understanding and Treatment of Mycosis

et al. 2017

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“…1). Amphotericin B and nystatin A 1 have serious liabilities including high toxicity and negligible oral bioavailability, and their continued use reflects the lack of better alternatives (11,12).…”

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confidence: 99%

Selvamicin, an atypical antifungal polyene from two alternative genomic contexts

Arnam

Ruzzini

Sit

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The bacteria harbored by fungus-growing ants produce a variety of small molecules that help maintain a complex multilateral symbiosis. In a survey of antifungal compounds from these bacteria, we discovered selvamicin, an unusual antifungal polyene macrolide, in bacterial isolates from two neighboring ant nests. Selvamicin resembles the clinically important antifungals nystatin A1 and amphotericin B, but it has several distinctive structural features: a noncationic 6-deoxymannose sugar at the canonical glycosylation site and a second sugar, an unusual 4-O-methyldigitoxose, at the opposite end of selvamicin’s shortened polyene macrolide. It also lacks some of the pharmacokinetic liabilities of the clinical agents and appears to have a different target. Whole genome sequencing revealed the putative type I polyketide gene cluster responsible for selvamicin’s biosynthesis including a subcluster of genes consistent with selvamicin’s 4-O-methyldigitoxose sugar. Although the selvamicin biosynthetic cluster is virtually identical in both bacterial producers, in one it is on the chromosome, in the other it is on a plasmid. These alternative genomic contexts illustrate the biosynthetic gene cluster mobility that underlies the diversity and distribution of chemical defenses by the specialized bacteria in this multilateral symbiosis.

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“…The MIC range for dermatophytes was 0.39‐3.12 µg/mL and for yeast was 0.78‐1.56 µg/mL, reinforcing the data from the screening that this compound is actually active at very low concentrations. In other studies, the presence of chlorine in chemical structures investigated as to the antifungal application has already been verified as determinant for effective activity . Structurally, the position of the chlorine is important for improving the antifungal action, since the substitution at positions meta and para of the disubstituted molecule 2j was more advantageous (lower MICs) than the substitution at ortho and para positions as for 2i (Figure ).…”

Section: Resultsmentioning

confidence: 85%

Discovery of a novel and selective fungicide that targets fungal cell wall to treat dermatomycoses: 1,3‐bis(3,4‐dichlorophenoxy)propan‐2‐aminium chloride

Lana

Lavorato

Giuliani

et al. 2019

Mycoses

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Summary Background Fungal infections are highly prevalent and are responsible for high rates of morbidity and mortality. In this context, the search for new treatment alternatives is very relevant. Objectives Analyse chemical compounds for antifungal potential against dermatomycosis fungi. Methods The antifungal activity of 121 compounds, intermediates or derivatives of 1,3‐bis(aryloxy)propane substituted at C‐2 (111 compounds) and isothiouronium derivatives (10 compounds) was investigated through susceptibility tests, mechanism of action, toxicity and hydrogel incorporation. Results The compound 1,3‐bis(3,4‐dichlorophenoxy)propan‐2‐aminium chloride (2j) was the most active fungicide against dermatophytes and Candida spp., at very low concentrations (0.39‐3.12 µg/mL), including action on resistant and multidrug‐resistant clinical strains. Compound 2j has presented a promising toxicity profile, showing selectivity index >10, relative to human lymphocytes. The compound was classified as non‐irritant by the HET‐CAM test and did not cause histopathological alterations in pig ear skin, thus presenting an excellent perspective for topical application. 2j targets the fungal cell wall, which was confirmed by scanning electron microscopy, which also indicated the additional ability of 2j to inhibit the Candida albicans pseudohyphae formation and biofilm of Microsporum canis. Compound 2j was incorporated in a hydrogel with bioadhesive potential. The results of the human skin permeation showed that 2j remained significantly in the epidermis, ideally for the dermatomycosis treatment. Conclusions Therefore, the compound 2j demonstrated the potential for antifungal drug development, with a action mechanism elucidated and already applied in a semisolid formulation as a new therapeutic option for fungal skin infections.

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A complex game of hide and seek: the search for new antifungals

Cited by 52 publications

References 193 publications

Antifungal Therapy: New Advances in the Understanding and Treatment of Mycosis

Antifungal Therapy: New Advances in the Understanding and Treatment of Mycosis

Selvamicin, an atypical antifungal polyene from two alternative genomic contexts

Discovery of a novel and selective fungicide that targets fungal cell wall to treat dermatomycoses: 1,3‐bis(3,4‐dichlorophenoxy)propan‐2‐aminium chloride

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