<i>In Vitro</i>
            Activities of Novel Azole Compounds ATTAF-1 and ATTAF-2 against Fluconazole-Susceptible and -Resistant Isolates of Candida Species

Fakhim, Hamed; Emami, Saeed; Vaezi, Afsane; Hashemi, Seyedeh Mahdieh; Faeli, Leila; Diba, Kambiz; Dannaoui, Éric; Badali, Hamid

doi:10.1128/aac.01106-16

Cited by 21 publications

(12 citation statements)

References 24 publications

(31 reference statements)

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“…Fluconazole is a fungistatic antifungal drug commonly used in the treatment of Candida infections, presenting an effective spectrum of activity against these pathogens (Mushi et al, 2018). Recently, studies involving newly azole base compounds (Motahari et al, 2018; Mahmoudi et al, 2019) and combination therapy (Fakhim et al, 2017) demonstrate its antifungal activity against C. albicans and non C. albicans species. However, due to its frequent use, fluconazole resistant strains have emerged (Akins, 2005; Morschhäuser, 2016).…”

Section: Discussionmentioning

confidence: 99%

Two New 1,3,4-Oxadiazoles With Effective Antifungal Activity Against Candida albicans

et al. 2019

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Candida infections have become a serious public health problem with high mortality rates, especially in immunocompromised patients, since Candida albicans is the major opportunistic pathogen responsible for systemic or invasive candidiasis. Commercially available antifungal agents are restricted and fungal resistance to such drugs has increased; therefore, the development of a more specific antifungal agent is necessary. Using assays for antifungal activity, here we report that two new compounds of 1,3,4-oxadiazoles class (LMM5 and LMM11), which were discovered by in silico methodologies as possible thioredoxin reductase inhibitors, were effective against C. albicans. Both compounds had in vitro antifungal activity with MIC 32 μg/ml. Cytotoxicity in vitro demonstrated that LMM5 and LMM11 were non-toxic in the cell lines evaluated. The kinetic of the time-kill curve suggested a fungistatic profile and showed an inhibitory effect of LMM5 and LMM11 in 12 h that remained for 24 and 36 h, which is better than fluconazole. In the murine systemic candidiasis model by C. albicans, the two compounds significantly reduced the renal and spleen fungal burden. According to the SEM and TEM images, we hypothesize that the mechanism of action of LMM5 and LMM11 is directly related to the inhibition of the enzyme thioredoxin reductase and internally affect the fungal cell. In view of all in vitro and in vivo results, LMM5 and LMM11 are effective therapeutic candidates for the development of new antifungal drugs addressing the treatment of human infections caused by C. albicans.

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Section: Discussionmentioning

confidence: 99%

Two New 1,3,4-Oxadiazoles With Effective Antifungal Activity Against Candida albicans

et al. 2019

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“…These results confirmed that RF3 exerted antifungal activities by disrupting membrane integrity. Compared with other kinds of novel antifungal agents that are designed base on the structure of FLU ( Fakhim et al, 2017 ), this non-specific physical membrane-disrupting mechanism of RF3 reduced the development of antifungal resistance. Studies indicate that ROS production is involved in antifungal mechanisms of certain peptides.…”

Section: Discussionmentioning

confidence: 99%

A Novel Dual-Targeted α-Helical Peptide With Potent Antifungal Activity Against Fluconazole-Resistant Candida albicans Clinical Isolates

et al. 2020

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Due to compromised immune system, fungal infection incidences have markedly increased in the last few decades. Pathogenic fungi have developed resistance to the clinically available antifungal agents. Antifungal resistance poses a great challenge to clinical treatment and has stimulated the demand for novel antifungal agents. A promising alternative to the treatment of fungal diseases is the use of antimicrobial peptides (AMPs). However, the antifungal activities of AMPs have not been fully determined. Therefore, this study aimed at designing and screening α-helical peptides with potential antifungal activities. The effects of key physicochemical parameters on antifungal activities were also investigated. A series of lengthened and residue-substituted derivatives of the template peptide KV, a hexapeptide truncated from the α-helical region of porcine myeloid antimicrobial peptide-36, were designed and synthesized. Enhancement of hydrophobicity by introducing aromatic hydrophobic amino acids (tryptophan and phenylalanine) significantly increased the efficacies of the peptides against Candida albicans strains, including fluconazole-resistant isolates. Increased hydrophobicity also elevated the toxic properties of these peptides. RF3 with moderate hydrophobicity exhibited potent anticandidal activities (GM = 6.96 μM) and modest hemolytic activities (HC10 > 64 μM). Additionally, repeated exposure to a subinhibitory concentration of RF3 did not induce resistance development. The antifungal mechanisms of RF3 were due to membrane disruptions and induction of reactive oxygen species production. Such a dual-targeted mechanism was active against drug-resistant fungi. These results show the important role of hydrophobicity and provide new insights into designing and developing antifungal peptides. Meanwhile, the successful design of RF3 highlights the potential utility of AMPs in preventing the spread of drug-resistant fungal infections.

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“…Within the same line azole-like molecules have also been obtained showing increased antifungal potency against all Candida species, compared to the efficacy exhibited by fluconazole [143]. These modified azoles, named ATTAF-1 and ATTAF-2, share general structural features with triazole alcohols, however, their mode of action appears to differ from the one of fluconazole which is an important trait to sensitize resistant strains [143]. Further on, Shrestha et al (2017) developed a series of 27 alkylated variants of fluconazole, some of which presented a low hemolytic activity, low cytotoxicity and strong inhibitory potential against several Candida species [144].…”

Section: Redesign Of "Old Antifungals"mentioning

confidence: 90%

“…The most paradigmatic examples are the new formulations of amphotericin B, which include lipid-associated and liposomal formulations showing higher fungal targeting and reduced toxicity against the host [142]. Within the same line azole-like molecules have also been obtained showing increased antifungal potency against all Candida species, compared to the efficacy exhibited by fluconazole [143]. These modified azoles, named ATTAF-1 and ATTAF-2, share general structural features with triazole alcohols, however, their mode of action appears to differ from the one of fluconazole which is an important trait to sensitize resistant strains [143].…”

Section: Redesign Of "Old Antifungals"mentioning

confidence: 99%

An Overview on Conventional and Non-Conventional Therapeutic Approaches for the Treatment of Candidiasis and Underlying Resistance Mechanisms in Clinical Strains

Salazar

Simões

Pedro

et al. 2020

JoF

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Fungal infections and, in particular, those caused by species of the Candida genus, are growing at an alarming rate and have high associated rates of mortality and morbidity. These infections, generally referred as candidiasis, range from common superficial rushes caused by an overgrowth of the yeasts in mucosal surfaces to life-threatening disseminated mycoses. The success of currently used antifungal drugs to treat candidiasis is being endangered by the continuous emergence of resistant strains, specially among non-albicans Candida species. In this review article, the mechanisms of action of currently used antifungals, with emphasis on the mechanisms of resistance reported in clinical isolates, are reviewed. Novel approaches being taken to successfully inhibit growth of pathogenic Candida species, in particular those based on the exploration of natural or synthetic chemicals or on the activity of live probiotics, are also reviewed. It is expected that these novel approaches, either used alone or in combination with traditional antifungals, may contribute to foster the identification of novel anti-Candida therapies.

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In Vitro Activities of Novel Azole Compounds ATTAF-1 and ATTAF-2 against Fluconazole-Susceptible and -Resistant Isolates of Candida Species

Cited by 21 publications

References 24 publications

Two New 1,3,4-Oxadiazoles With Effective Antifungal Activity Against Candida albicans

Two New 1,3,4-Oxadiazoles With Effective Antifungal Activity Against Candida albicans

A Novel Dual-Targeted α-Helical Peptide With Potent Antifungal Activity Against Fluconazole-Resistant Candida albicans Clinical Isolates

An Overview on Conventional and Non-Conventional Therapeutic Approaches for the Treatment of Candidiasis and Underlying Resistance Mechanisms in Clinical Strains

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