Drug Repurposing in Medical Mycology: Identification of Compounds as Potential Antifungals to Overcome the Emergence of Multidrug-Resistant Fungi

Peyclit, Lucie; Yousfi, Hanane; Rolain, Jean‐Marc; Bittar, Fadi

doi:10.3390/ph14050488

Cited by 33 publications

(30 citation statements)

References 135 publications

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“…These data suggest that the efficacy of AMB for the treatment of invasive C. auris infections, including meningitis, endophthalmitis, and urinary tract infections, cannot be reliably predicted using MIC results, which may explain the high mortality with AMB treatment [ 3 , 4 ]. Although a combination of echinocandins with AMB may improve survival [ 13 ], the discovery of new antifungal agents with traditional or new targets is essential to improve the survival rate of infections by multiresistant fungi, including C. auris [ 24 , 25 , 26 ].…”

Section: Discussionmentioning

confidence: 99%

Unpredictable In Vitro Killing Activity of Amphotericin B against Four Candida auris Clades

et al. 2021

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Candida auris is an emerging multiresistant yeast against which amphotericin B (AMB) is still the first therapeutic choice in certain clinical situations (i.e., meningitis, endophthalmitis, and urinary tract infections). As data about the in vitro killing activity of AMB against C. auris clades are lacking, we determined MICs, minimum fungicidal concentrations (MFCs), and killing activity of AMB against 22 isolates representing the 4 major C. auris clades (South Asian n = 6; East Asian n = 4; South African n = 6, and South American n = 6). MIC values were ≤1 mg/L regardless of clades; MFC ranges were, 1–4 mg/L, 2–4 mg/L, 2 mg/L, and 2–8 mg/L for South Asian, East Asian, South African, and South American clades, respectively. AMB showed concentration-, clade-, and isolate-dependent killing activity. AMB was fungicidal at 1 mg/L against two of six, two of four, three of six, and one of six isolates from the South Asian, East Asian, South African, and South American clades, respectively. Widefield fluorescence microscopy showed cell number decreases at 1 mg/L AMB in cases of the South Asian, East Asian, and South African clades. These data draw attention to the weak killing activity of AMB against C. auris regardless of clades, even when MICs are low (≤1 mg/L). Thus, AMB efficacy is unpredictable in treatment of invasive C. auris infections.

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Section: Discussionmentioning

confidence: 99%

Unpredictable In Vitro Killing Activity of Amphotericin B against Four Candida auris Clades

et al. 2021

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“…The available antifungals are not efficient in eradicating biofilm-related infections [ 59 , 60 , 61 ], and the emergence of multi-resistant fungal strains [ 62 , 63 , 64 ] has become a serious health concern in this century [ 65 , 66 ]. In recent years, the search for new therapeutic approaches with different targets or mechanisms of action has been constantly evolving [ 64 , 67 ], and several authors have proposed AMPs, and temporins, as promising scaffolds for the development of new antifungal compounds [ 13 , 14 , 16 , 23 , 24 , 25 , 68 ]. Our group and others have described the antifungal activity of temporins L and B [ 69 , 70 ].…”

Section: Discussionmentioning

confidence: 99%

Antifungal Activity of the Frog Skin Peptide Temporin G and Its Effect on Candida albicans Virulence Factors

D’Auria

Casciaro

Angelis

et al. 2022

IJMS

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The increasing resistance to conventional antifungal drugs is a widespread concern, and a search for new compounds, active against different species of fungi, is demanded. Antimicrobial peptides (AMPs) hold promises in this context. Here we investigated the activity of the frog skin AMP Temporin G (TG) against a panel of fungal strains, by following the Clinical and Laboratory Standards Institute protocols. TG resulted to be active against (i) Candida species and Cryptococcus neoformans, with MIC50 between 4 µM and 64 µM after 24 h of incubation; (ii) dermatophytes with MIC80 ranging from 4 to 32 µM, and (iii) Aspergillus strains with MIC80 of 128 µM. In addition, our tests revealed that TG reduced the metabolic activity of Candida albicans cells, with moderate membrane perturbation, as proven by XTT and Sytox Green assays, respectively. Furthermore, TG was found to be effective against some C. albicans virulence factors; indeed, at 64 µM it was able to inhibit ~90% of yeast–mycelial switching, strongly prevented biofilm formation, and led to a 50% reduction of metabolic activity in mature biofilm cells, and ~30–35% eradication of mature biofilm biomass. Even though further studies are needed to deepen our knowledge of the mechanisms of TG antifungal activity, our results suggest this AMP as an attractive lead compound for treatment of fungal diseases.

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“…It inhibits fungal protein synthesis after being converted to 5-fluorouracil by cytosine deaminase and incorporated into fungal RNA, replacing uridylic acid. It is also a potent inhibitor of fungal DNA synthesis through the inhibition of thymidylate synthetase [ 160 , 161 ]. The drug is effective against a wide range of Candida spp., is well tolerated, and has a synergistic effect with amphotericin B. Flucytosine is used in combination with amphotericin B in invasive candidiasis in neonates with Candida meningitis due to its superb penetration into the cerebrospinal fluid.…”

Section: Treatment Of Invasive Candidiasismentioning

confidence: 99%

Diagnosis and Treatment of Invasive Candidiasis

Barantsevich

2022

Antibiotics

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Candida species, belonging to commensal microbial communities in humans, cause opportunistic infections in individuals with impaired immunity. Pathogens encountered in more than 90% cases of invasive candidiasis include C. albicans, C. glabrata, C. krusei, C. tropicalis, and C. parapsilosis. The most frequently diagnosed invasive infection is candidemia. About 50% of candidemia cases result in deep-seated infection due to hematogenous spread. The sensitivity of blood cultures in autopsy-proven invasive candidiasis ranges from 21% to 71%. Non-cultural methods (beta-D-glucan, T2Candida assays), especially beta-D-glucan in combination with procalcitonin, appear promising in the exclusion of invasive candidiasis with high sensitivity (98%) and negative predictive value (95%). There is currently a clear deficiency in approved sensitive and precise diagnostic techniques. Omics technologies seem promising, though require further development and study. Therapeutic options for invasive candidiasis are generally limited to four classes of systemic antifungals (polyenes, antimetabolite 5-fluorocytosine, azoles, echinocandins) with the two latter being highly effective and well-tolerated and hence the most widely used. Principles and methods of treatment are discussed in this review. The emergence of pan-drug-resistant C. auris strains indicates an insufficient choice of available medications. Further surveillance, alongside the development of diagnostic and therapeutic methods, is essential.

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Drug Repurposing in Medical Mycology: Identification of Compounds as Potential Antifungals to Overcome the Emergence of Multidrug-Resistant Fungi

Cited by 33 publications

References 135 publications

Unpredictable In Vitro Killing Activity of Amphotericin B against Four Candida auris Clades

Unpredictable In Vitro Killing Activity of Amphotericin B against Four Candida auris Clades

Antifungal Activity of the Frog Skin Peptide Temporin G and Its Effect on Candida albicans Virulence Factors

Diagnosis and Treatment of Invasive Candidiasis

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