Antifungal Activity of Fibrate-Based Compounds and Substituted Pyrroles That Inhibit the Enzyme 3-Hydroxy-methyl-glutaryl-CoA Reductase of
            <i>Candida glabrata</i>
            (CgHMGR), Thus Decreasing Yeast Viability and Ergosterol Synthesis

Madrigal-Aguilar, Damián A.; Gonzalez-Silva, Adilene; Rosales-Acosta, Blanca; Bautista-Crescencio, Celia; Ortiz‐Álvarez, Jossue; Escalante, Carlos H.; Sánchez-Navarrete, Jaime; Hernández‐Rodríguez, César; Chamorro-Cevallos, Germán; Tamariz, Joaquı́n; Villa‐Tanaca, Lourdes

doi:10.1128/spectrum.01642-21

Cited by 11 publications

(22 citation statements)

References 35 publications

(79 reference statements)

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“…The growth recovery of C. glabrata with mevalonate, squalene, and ergosterol suggests that the S. albidoflavus Q metabolites affect the first module of the ergosterol biosynthetic pathway ( Fig. 1 ) ( 21 , 23 , 24 , 29 ). C. albicans ATCC 10231 did not show growth recovery with ergosterol, perhaps because of the distinct sterol uptake responses between yeasts like Schizosaccharomyces pombe, C. glabrata , and C. albicans ( 30 ).…”

Section: Discussionmentioning

confidence: 99%

“…C. albicans ATCC 10231 did not show growth recovery with ergosterol, perhaps because of the distinct sterol uptake responses between yeasts like Schizosaccharomyces pombe, C. glabrata , and C. albicans ( 30 ). On the contrary, the difference between the C. glabrata CBS 138 and CGL 43 strains in regard to growth recovery with mevalonate might be associated with the distinct genetic background of the two strains, the first of which is susceptible and the second is resistant to fluconazole ( 23 ). The regulation of the ergosterol biosynthesis pathway could vary from one Candida species to another ( 24 , 30 ).…”

Section: Discussionmentioning

confidence: 99%

“…Hence, this compound could possibly compete with NADPH, the natural cofactor of the enzyme. Regarding compound 2, synthetic substituted pyrroles are known to act as antifungals by inhibiting Cg HMGR activity and ergosterol synthesis ( 23 ).…”

Section: Discussionmentioning

confidence: 99%

“…The modified microplate dilution method described by the Clinical and Laboratory Standards Institute (CLSI) was used to determine the minimum inhibitory concentration (MIC) of the lyophilized supernatant of S. albidoflavus Q ( 23 , 66 ). Briefly, stock solutions were prepared with the lyophilized supernatant in RPMI 1640 medium (Sigma-Aldrich).…”

Section: Methodsmentioning

confidence: 99%

“…Cg HMGR has been proposed as an alternative therapeutic target for new antifungals ( 20 – 23 ). It participates in the mevalonate biosynthesis pathway, the first module of the ergosterol biosynthesis pathway ( Fig.…”

Section: Introductionmentioning

confidence: 99%

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Streptomyces albidoflavus Q antifungal metabolites inhibit the ergosterol biosynthesis pathway and yeast growth in fluconazole-resistant Candida glabrata : phylogenomic and metabolomic analyses

Bautista-Crescencio,

Casimiro-Ramos,

Fragoso-Vázquez

et al. 2023

Microbiol Spectr

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There is an urgent need to develop new antifungals due to the increasing prevalence of multidrug-resistant fungal infections and the recent emergence of COVID-19-associated candidiasis. A good study model for evaluating new antifungal compounds is Candida glabrata , an opportunistic fungal pathogen with intrinsic resistance to azoles (the most common clinical drugs for treating fungal infections). The aim of the current contribution was to conduct in vitro tests of antifungal metabolites produced by the bacteria Streptomyces albidoflavus Q, identify their molecular structures, and utilize several techniques to provide evidence of their therapeutic target. S. albidoflavus was isolated from maize rhizospheric soil in Mexico and identified by phylogenomic analysis using a 92-gene core. Of the 66 metabolites identified in S. albidoflavus Q by a liquid chromatography-high resolution mass spectrometry (LC-HRMS) metabolomic analysis of the lyophilized supernatant, six were selected by the Way2drug server based on their in silico binding to the likely target, 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGR, the key enzyme in the ergosterol biosynthesis pathway). Molecular modeling studies show a relatively high binding affinity for the Cg HMGR enzyme by two secondary metabolites: isogingerenone B (diaryl heptanoid) and notoginsenoside J (polycyclic triterpene). These secondary metabolites were able to inhibit ergosterol synthesis and affect yeast viability in vitro . They also caused alterations in the ultrastructure of the yeast cytoplasmic membrane, as evidenced by transmission electron microscopy. The putative target of isogingerenone B and notoginsenoside J is distinct from that of azole drugs (the most common clinical antifungals). The target for the latter is the lanosterol 14 alpha-demethylase enzyme (Erg11). IMPORTANCE Multidrug resistance has emerged among yeasts of the genus Candida , posing a severe threat to global health. The problem has been exacerbated by the pandemic associated with COVID-19, during which resistant strains of Candida auris and Candida glabrata have been isolated from patients infected with the SARS-CoV-2 virus. To confront this challenge, the World Health Organization has invoked scientists to search for new antifungals with alternative molecular targets. This study identified 66 metabolites produced by the bacteria Streptomyces albidoflavus Q, 6 of which had promising properties for potential antifungal activity. The metabolites were tested in vitro as inhibitors of ergosterol synthesis and C. glabrata growth, with positive results. They were also found to damage the cytoplasmic membrane of the fungus. The corresponding molecular structures and their probable therapeutic target were established. The target is apparently distinct from that of azole drugs.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Streptomyces albidoflavus Q antifungal metabolites inhibit the ergosterol biosynthesis pathway and yeast growth in fluconazole-resistant Candida glabrata : phylogenomic and metabolomic analyses

Bautista-Crescencio,

Casimiro-Ramos,

Fragoso-Vázquez

et al. 2023

Microbiol Spectr

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Pyrrole: An Essential Framework in the Development of Therapeutic Agents and Insightful Analysis of Structure‐Active Relationships

Sahu,

Gidwani

et al. 2024

ChemistrySelect

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Pyrrole is a heterocyclic structure with diverse pharmacophores, enabling the creation of an extensive lead molecule library. Its broad range of pharmacological profiles has concerned significant global research interests. This review highlights recent advancements in pyrrole scaffolds, focusing on their structure active relationship and bioactivities. Pyrrole derivatives recognized for their biological activities, are promising scaffolds for developing antimicrobial, antimalarial, antiviral, antituberculosis, and enzyme‐inhibiting properties. Their unique anti‐inflammatory and antioxidant features have prompted the development of novel cardioprotective and neuroprotective compounds. The review aims to elucidate the SAR of pyrrole mimics, aiding future therapeutic developments.

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COVID-19-associated candidiasis and the emerging concern of Candida auris infections

Tsai

Lee

Chen

et al. 2023

Journal of Microbiology, Immunology and Infection

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Antifungal Activity of Fibrate-Based Compounds and Substituted Pyrroles That Inhibit the Enzyme 3-Hydroxy-methyl-glutaryl-CoA Reductase of Candida glabrata (CgHMGR), Thus Decreasing Yeast Viability and Ergosterol Synthesis

Cited by 11 publications

References 35 publications

Streptomyces albidoflavus Q antifungal metabolites inhibit the ergosterol biosynthesis pathway and yeast growth in fluconazole-resistant Candida glabrata : phylogenomic and metabolomic analyses

Streptomyces albidoflavus Q antifungal metabolites inhibit the ergosterol biosynthesis pathway and yeast growth in fluconazole-resistant Candida glabrata : phylogenomic and metabolomic analyses

Pyrrole: An Essential Framework in the Development of Therapeutic Agents and Insightful Analysis of Structure‐Active Relationships

COVID-19-associated candidiasis and the emerging concern of Candida auris infections

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