Are the Statins promising antifungal agents against invasive candidiasis?

Lima, William Gustavo; Alves-Nascimento, Lídia Anita; Andrade, Jéssica Tauany; Vieira, Letícia; Ribeiro, Rosy Iara Maciel de Azambuja; Thomé, Ralph Gruppi; Santos, Hélio Batista dos; Ferreira, Jaqueline Maria Siqueira; Soares, Adriana Cristina

doi:10.1016/j.biopha.2018.12.076

Cited by 52 publications

(47 citation statements)

References 47 publications

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“…However, the pitavastatin-fluconazole combination was ineffective against C. albicans strains SC-MRR1 R34A and TWO7241 which have been reported as MFS-efflux hyperactive strains [35-37]. Moreover, the interruption of ergosterol biosynthesis often results in a fungistatic activity, which does not explain the fungicidal activity displayed by statins, as reported by others [38]. Accordingly, Lima et al proposed the existence of additional mechanisms by which statins induced their antifungal activities.…”

Section: Discussionmentioning

confidence: 99%

Repurposing approach identifies phenylpentanol derivatives as potent azole chemosensitizing agents effective against azole-resistant Candida species

Eldesouky

Salama

et al. 2019

Preprint

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26The limited number of systemic antifungals and the emergence of azole-resistant Candida 27 species constitute a growing challenge to human medicine. Combinatorial drug therapy represents 28 an appealing approach to enhance the activity of, or restore the susceptibility to current antifungals. 29 Here, we evaluated the fluconazole chemosensitization activity of the Pharmakon 1600 drug 30 library against azole-resistant Candida albicans. We identified 33 non-antifungal drugs that were 31 able to restore susceptibility to fluconazole in an azole-resistant C. albicans. Structural 32 investigation of identified hits revealed phenylpentanol scaffold as a valuable pharmacophore for 33 re-sensitizing azole-resistant Candida species to the effect of current azole antifungal drugs. All 34 phenylpentanol derivatives displayed potent fluconazole chemosensitizing activities (ΣFICI 0.13-35 0.28) and were able to reduce fluconazole's MIC by 15-31 fold against the tested strain. 36Particularly pitavastatin displayed the most potent fluconazole chemosensitizing activity (ΣFICI 37 0.06-0.50). The pitavastatin-fluconazole combination displayed a broad-spectrum synergistic 38 relationship against 90% of the tested strains, including strains of C. albicans, C. glabrata, and C. 39 auris. Moreover, pitavastatin restored the susceptibility of the multidrug-resistant C. auris to the 40 antifungal activities of itraconazole and voriconazole. Additionally, the pitavastatin-fluconazole 41 combination significantly reduced the biofilm-forming abilities of the tested Candida species and 42 successfully reduced the fungal burdens in a Caenorhabditis elegans infection model. Both 43 pitavastatin and the plain phenylpentanol scaffold were able to interfere significantly with 44 Candida's efflux activities as demonstrated by Nile Red efflux assays and flow cytometry. This 45 study presents phenylpentanol derivatives as potent azole chemosensitizers that warrant further 46 investigation. 47 3 48 Introduction 49 Candidiasis is a leading cause of healthcare-associated bloodstream infections and is 50 associated with high morbidities and mortalities. Infections caused by Candida species can range 51 from uncomplicated self-limited superficial infections of mucosal membranes to deadly 52 disseminated bloodstream and deep-seated tissue infections often associated with a mortality rate 53 of 42 -65% [1]. Current epidemiological data portrays C. albicans and C. glabrata as the major 54 causes of Candida-related infections [2-5]. However, the recent emergence of new Candida 55 species, such as multidrug-resistant C. auris is expected to impact the current epidemiological 56 trends [6-8]. 57 Additionally, Candida species are known for their remarkable capabilities of forming 58 robust adherent structures (i.e., biofilms) on surfaces of different abiotic surfaces, such as 59 catheters, and medical implants [9-11]. Biofilms limit the penetration of antifungal drugs and can 60 contribute to treatment failure and chronic infections [12]. Fungal cell...

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Section: Discussionmentioning

confidence: 99%

Repurposing approach identifies phenylpentanol derivatives as potent azole chemosensitizing agents effective against azole-resistant Candida species

Eldesouky

Salama

et al. 2019

Preprint

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“…There are indeed several reports showing that statins influence the diversity of the human gut microbiota [18,[55][56][57]. In addition, although the research on the antibacterial activity of FLU has been scarce and more studies are needed [58], it seems that its antifungal activity may be higher than that of other statins [59]. In another study, administration of ROS to mice randomly in the diet for 28 days significantly influenced the structure of the gut microbiota [17].…”

Section: Plos Onementioning

confidence: 98%

An in vitro evaluation of the effects of different statins on the structure and function of human gut bacterial community

Zhao

Chen

et al. 2020

PLoS ONE

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Statins, a class of drugs that can effectively remove cholesterol from serum, are used to regulate plasma total cholesterol and reduce the risk of cardiovascular diseases, but it is still unclear whether the drug are modulated by gut microbiota or the structures of gut microbiota are shaped by statins. We investigated the interactions between statins and the human gut microbiota during the in vitro fermentation process by 16S rRNA gene sequencing, gas chromatography (GC), and high-performance liquid chromatography (HPLC) analyses. The presence of fluvastatin (FLU2) specifically promoted the growth of Escherichia/Shigella, Ruminococcaceae UCG 014, and Sutterella. However, the composition of the gut bacterial microbiota remained relatively static in samples treated with rosuvastatin (ROS), simvastatin (SIM), and atorvastatin (ATO). The PICRUSt program predicted moderate differences in the functional categories related to the biosynthesis of other secondary metabolites, cellular processes and signaling, and signal transduction in the FLU2 fermentation samples. Our study revealed substantial variation in the structure and function of microbiomes from the FLU2-treated samples. In addition, short-chain fatty acids (SCFAs) were also significantly decreased in FLU2-treated samples compared with the samples treated with other stains. Statins can be degraded by the human gut microbiota in vitro, and the degradation rate was approximately 7%-30% and 19%-48% after fermentation was allowed to proceed for 24 h and 48 h, respectively. Generally, FLU2 could largely shape the composition and function of human gut microbiota, which resulted in changes in the production of SCFAs. In turn, all statins could be degraded or modified by the gut microbiota. Our study paves the way for elucidating statin-gut microbiota interactions in vitro towards the improvement of the host health and personalized medicine.

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“…Thus, the selectivity index (SI) was calculated through the ratio between the CC 50 of compounds against the hamster spleen cells and the geometric mean (GM) of IC 50 values calculated for L. (V.) braziliensis and L. (L.) infantum. 21 In the case where CC 50 was higher than the highest concentration tested of the compound, to calculate the SI, the value used was 400. The larger SI was indicative of a safer molecule.…”

Section: Selective Index (Si) Determinationmentioning

confidence: 99%

Toxicity and Anti-promastigote Activity of Benzoxazinoid Analogs Against Leishmania (Viannia) braziliensis and Leishmania (Leishmania) infantum

et al. 2019

Self Cite

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Purpose: Here, we aim to evaluate the antileishmanial activity of compounds with a benzoxazinoid (BX) skeleton, previously synthesized by our group, against Leishmania (Viannia) braziliensis and Leishmania (Leishmania) infantum promastigotes. Methods: Anti-promastigote activity, as well as cytotoxicity, were determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) colorimetric assays. The selectivity index (SI) for each compound was calculated using a ratio of the cytotoxicity of compounds and the geometric mean (GM) of antileishmanial concentrations to each species tested. The comparisons between groups were carried out using a t test or analysis of variance (one-way ANOVA). A P value of less than 0.05 was considered significant. Results: All the compounds tested were active, with IC50 falling between 92±6.19 µg/mL and 238±6.57 µg/mL for L. braziliensis, and 89±6.43 µg/mL and 188±3.58 µg/mL against L. infantum. Bex2, Bex3, Pyr1, Pyr2, and Pyr4 were compounds that showed activity similar to the drug Glucantime®, exhibited low cytotoxicity against splenic hamster cells (CC50 raging between >400 and 105.7±2.26 µg/mL) and had favorable selectivity indices (SI 1.12 to 3.96). Conclusion: The analogs in question are promising prototypes for the pharmaceutical development of novel, safer and more effective leishmanicidal agents.

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Are the Statins promising antifungal agents against invasive candidiasis?

Cited by 52 publications

References 47 publications

Repurposing approach identifies phenylpentanol derivatives as potent azole chemosensitizing agents effective against azole-resistant Candida species

Repurposing approach identifies phenylpentanol derivatives as potent azole chemosensitizing agents effective against azole-resistant Candida species

An in vitro evaluation of the effects of different statins on the structure and function of human gut bacterial community

Toxicity and Anti-promastigote Activity of Benzoxazinoid Analogs Against Leishmania (Viannia) braziliensis and Leishmania (Leishmania) infantum

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