Recent advances in antifungal drug development targeting lanosterol 14α‐demethylase (<scp>CYP51</scp>): A comprehensive review with structural and molecular insights

Singh, Atamjit; Singh, Kunal; Sharma, Aman; Kaur, Kirandeep; Chadha, Renu; Bedi, Preet Mohinder Singh

doi:10.1111/cbdd.14266

Cited by 11 publications

(4 citation statements)

References 137 publications

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“…Antifungal drug resistance and the emergence of intrinsically resistant fungal strains and species to conventional drugs is a concerning threat that has been growing in recent years, 69 and the development of new antifungal drugs is paramount. 70 Based on our results, it is tempting to speculate that the combination of antifungal drugs with inhibitors of the N -linked mannosylation pathway may affect both biofilm formation and susceptibility to antifungal drugs. Currently, some drugs that inhibit enzymes of the protein N -linked glycosylation pathway in humans have been experimentally used, such as inhibitors of endoplasmic reticulum glycosidases.…”

Section: Discussionmentioning

confidence: 80%

Contribution of N-Linked Mannosylation Pathway to Candida parapsilosis and Candida tropicalis Biofilm Formation

Clavijo-Giraldo,

Pérez-García,

Hernández-Chávez

et al. 2023

IDR

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Background Mycoses are a growing threat to human health, and systemic candidiasis caused by Candida parapsilosis and Candida tropicalis is frequent in immunocompromised patients. Biofilm formation is a virulence factor found in these organisms, as sessile cells adhere to surfaces, the stratification and production of extracellular matrix provides protection and resistance to antifungal drugs. Previous evidence indicated that the N -linked mannosylation pathway is relevant to C. albicans biofilms, but its contribution to other species remains unknown. Methods C. parapsilosis and C. tropicalis och1 ∆ mutants, which have a disrupted N -linked mannosylation pathway, were used to form biofilms. In addition, wild-type and mutant cells were also treated to remove N -linked mannans or block this pathway. Biofilms were analyzed by quantifying the included fungal biomass, and extracellular matrix components. Moreover, gene expression and secreted hydrolytic enzymes were also quantified in these biofilms. Results The och1 ∆ mutants showed a reduced ability to form biofilms in both fungal species when compared to the wild-type and control strains. This observation was confirmed by trimming N -linked mannans from walls or blocking the pathway with tunicamycin B. According to this observation, mutant, and treated cells showed an altered composition of the extracellular matrix and increased susceptibility to antifungal drugs when compared to control or untreated cells. The gene expression of secreted virulence factors, such as aspartyl proteinases and phospholipases, was normal in all the tested cells but the secreted activity was reduced, suggesting a defect in the secretory pathway, which was later confirmed by treating cells with brefeldin A. Conclusion Proper N -linked mannosylation is required for biofilm formation in both C. parapsilosis and C. tropicalis . Disruption of this posttranslational modification affected the secretory pathway, offering a link between glycosylation and biofilm formation.

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Section: Discussionmentioning

confidence: 80%

Contribution of N-Linked Mannosylation Pathway to Candida parapsilosis and Candida tropicalis Biofilm Formation

Clavijo-Giraldo,

Pérez-García,

Hernández-Chávez

et al. 2023

IDR

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“…Lanosterol is converted to zymosterol via two intermediates, 4,4-dimethyl-zymosterol-8,14,24-trienol and 4,4-dimethyl-zymosterol, by lanosterol 14α-demethylase (ERG11) and sterol C14-reductase (ERG24). Azoles were identified as effective inhibitors of ERG11 (Table 5) via selective coordination with heme iron [397,398] and demonstrated striking antifungal activity against a variety of human fungal pathogens [399,400]. Importantly, azoles inhibit human lanosterol 14α-demethylase at substantially higher concentrations than the fungal enzyme [397].…”

Section: Ergosterol Synthesismentioning

confidence: 99%

Lipid-Centric Approaches in Combating Infectious Diseases: Antibacterials, Antifungals and Antivirals with Lipid-Associated Mechanisms of Action

Ostroumova,

Efimova

2023

Antibiotics

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One of the global challenges of the 21st century is the increase in mortality from infectious diseases against the backdrop of the spread of antibiotic-resistant pathogenic microorganisms. In this regard, it is worth targeting antibacterials towards the membranes of pathogens that are quite conservative and not amenable to elimination. This review is an attempt to critically analyze the possibilities of targeting antimicrobial agents towards enzymes involved in pathogen lipid biosynthesis or towards bacterial, fungal, and viral lipid membranes, to increase the permeability via pore formation and to modulate the membranes’ properties in a manner that makes them incompatible with the pathogen’s life cycle. This review discusses the advantages and disadvantages of each approach in the search for highly effective but nontoxic antimicrobial agents. Examples of compounds with a proven molecular mechanism of action are presented, and the types of the most promising pharmacophores for further research and the improvement of the characteristics of antibiotics are discussed. The strategies that pathogens use for survival in terms of modulating the lipid composition and physical properties of the membrane, achieving a balance between resistance to antibiotics and the ability to facilitate all necessary transport and signaling processes, are also considered.

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“…14 Among these, fluconazole and voriconazole have been extensively used for the management of C. albicans infections for their ability to interrupt the biosynthesis of ergosterol, a key fungal-specific membrane sterol, by targeting and inhibiting the lanosterol 14α-demethylase (CYP51), a cytochrome P450 enzyme that catalyzes a key step reaction on the pathway of the conversion of lanosterol to ergosterol, encoded by the ERG11 (Cyp51) gene. 15 However, in recent years, the emergence of azoles resistance due to the mutation of drug target genes ERG11 and ERG3, 16 the upregulation of drug efflux genes CDR1 and CDR2 alongside the side effects of the available antifungals showed that a knowledge void persists in the search for novel antifungal agents effective against resistant antifungal strains, especially nonazole compounds targeting key steps of ergosterol biosynthesis. 17,18 The quest for expanding the antifungal toolbox should focus on the identification of new chemical entities acting as antifungal agents, but it should also not neglect the possibility to discover new compounds able to synergize their activity on resistant fungal strains.…”

Section: ■ Introductionmentioning

confidence: 99%

A First-in-Class Pyrazole-isoxazole Enhanced Antifungal Activity of Voriconazole: Synergy Studies in an Azole-Resistant Candida albicans Strain, Computational Investigation and in Vivo Validation in a Galleria mellonella Fungal Infection Model

Pelliccia,

Russomanno,

Barone

et al. 2024

J. Med. Chem.

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The widespread and irrational use of azole antifungal agents has led to an increase of azole-resistant Candida albicans strains with an urgent need for combination drug therapy, enhancing the treatment efficacy. Here, we report the discovery of a first-in-class pyrazole-isoxazole, namely, 5b, that showed remarkable growth inhibition against the C. albicans ATCC 10231 strain in combination with voriconazole, acting as a downregulator of ERG 11 (Cyp51) gene expression with a significant reduction of the yeast-to-hypha morphological transition. Furthermore, C. albicans CYP51 enzyme assay and in-depth molecular docking studies unveiled the unique ability of the combination of 5b and voriconazole to completely fill the CYP51 binding sites. In vivo studies using a Galleria mellonella model confirmed the previously in vitro observed synergistic effect of 5b with voriconazole. Also considering its biocompatibility in a cellular model of human keratinocytes, these results indicate that 5b represents a promising compound for a further optimization campaign.

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Recent advances in antifungal drug development targeting lanosterol 14α‐demethylase (CYP51): A comprehensive review with structural and molecular insights

Cited by 11 publications

References 137 publications

Contribution of N-Linked Mannosylation Pathway to Candida parapsilosis and Candida tropicalis Biofilm Formation

Contribution of N-Linked Mannosylation Pathway to Candida parapsilosis and Candida tropicalis Biofilm Formation

Lipid-Centric Approaches in Combating Infectious Diseases: Antibacterials, Antifungals and Antivirals with Lipid-Associated Mechanisms of Action

A First-in-Class Pyrazole-isoxazole Enhanced Antifungal Activity of Voriconazole: Synergy Studies in an Azole-Resistant Candida albicans Strain, Computational Investigation and in Vivo Validation in a Galleria mellonella Fungal Infection Model

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