The Anticancer Drug Bleomycin Shows Potent Antifungal Activity by Altering Phospholipid Biosynthesis

Pokharel, Mona; Konarzewska, Paulina; Roberge, Jacques Y.; Han, Gil‐Soo; Wang, Yina; Carman, George M.; Xue, Chaoyang

doi:10.1128/spectrum.00862-22

Cited by 5 publications

(5 citation statements)

References 52 publications

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“…Bleomycin is an FDA‐approved anticancer drug widely utilized for the treatment of head and neck cancer, testicular cancer, cervical cancer, uterine cancer, and other malignancies [43,44] . This clearly indicates that the CS‐AgNPs synthesized in this study could be potentially utilized as an effective anticancer agent.…”

Section: Discussionmentioning

confidence: 62%

Synthesis of Silver Nanoparticles Using Camellia sinensis Leaf Extract: Promising Particles for the Treatment of Cancer and Diabetes

Hosen,

Rahman,

Rahman

et al. 2024

Chemistry & Biodiversity

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Both diabetes and cancer pose significant threats to public health. To overcome these challenges, nanobiotechnology offers innovative solutions for the treatment of these diseases. However, the synthesis of nanoparticles can be complex, costly and environmentally toxic. Therefore, in this study, we successfully synthesized Camellia sinensis silver nanoparticles (CS‐AgNPs) biologically from methanolic leaf extract of C. sinensis and as confirmed by the visual appearance which exhibited strong absorption at 456 nm in UV‐visible spectroscopy. The fourier transform infrared spectroscopy (FTIR) analysis revealed that phytochemicals of C. sinensis were coated with AgNPs. Scanning electron microscopy (SEM) analysis showed the spherical shape of CS‐AgNPs, with a size of 15.954 nm, while X‐ray diffraction spectrometry (XRD) analysis detected a size of 20.32 nm. Thermogravimetric analysis (TGA) indicated the thermal stability of CS‐AgNPs. The synthesized CS‐AgNPs significantly inhibited the ehrlich ascites carcinoma (EAC) cell growth with 53.42±1.101 %. The EAC cell line induced mice exhibited increased level of the serum aspartate aminotransferase (AST), alanine transaminase (ALT), and alkaline phosphatase (ALP), however this elevated serum parameter significantly reduced and controlled by the treatment with CS‐AgNPs. Moreover, in a streptozotocin‐induced diabetic mice model, CS‐AgNPs greatly reduced blood glucose, total cholesterol, triglyceride, low‐density lipoprotein (LDL) and creatinine levels. These findings highlight that the synthesized CS‐AgNPs have significant anticancer and antidiabetic activities that could be used as promising particles for the treatment of these major diseases. However, pre‐clinical and clinical trial should be addressed before use this particles as therapeutics agents.

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Section: Discussionmentioning

confidence: 62%

Synthesis of Silver Nanoparticles Using Camellia sinensis Leaf Extract: Promising Particles for the Treatment of Cancer and Diabetes

Hosen,

Rahman,

Rahman

et al. 2024

Chemistry & Biodiversity

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“…Currently, despite the fact that PS synthase is a promising drug target, the identification of its specific inhibitors is in the early stage. Two cell-based screens were conducted to identify inhibitors of C. albicans PS synthase, but both attempts were unsuccessful [ 244 , 245 ]. One screen pinpointed the compound SB-224289.…”

Section: Cell Membrane Biosynthesis Enzymesmentioning

confidence: 99%

“…However, it was later determined that SB-224289 only acts on PS synthase-related physiological pathways rather than the enzyme directly [ 244 ]. The other screen identified bleomycin, but it was also found that this compound affects phospholipid-associated processes rather than targeting C. albicans PS synthase directly [ 245 ]. Recently, Zhou et al identified a molecule, CBR-5884 ( Table 3 ), that inhibits both purified PS synthase and its function in vivo, with a K i of 1550 ± 245.6 nM [ 121 ].…”

Section: Cell Membrane Biosynthesis Enzymesmentioning

confidence: 99%

Innovations in Antifungal Drug Discovery among Cell Envelope Synthesis Enzymes through Structural Insights

Zhou,

Reynolds

2024

JoF

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Life-threatening systemic fungal infections occur in immunocompromised patients at an alarming rate. Current antifungal therapies face challenges like drug resistance and patient toxicity, emphasizing the need for new treatments. Membrane-bound enzymes account for a large proportion of current and potential antifungal targets, especially ones that contribute to cell wall and cell membrane biosynthesis. Moreover, structural biology has led to a better understanding of the mechanisms by which these enzymes synthesize their products, as well as the mechanism of action for some antifungals. This review summarizes the structures of several current and potential membrane-bound antifungal targets involved in cell wall and cell membrane biosynthesis and their interactions with known inhibitors or drugs. The proposed mechanisms of action for some molecules, gleaned from detailed inhibitor–protein studeis, are also described, which aids in further rational drug design. Furthermore, some potential membrane-bound antifungal targets with known inhibitors that lack solved structures are discussed, as these might be good enzymes for future structure interrogation.

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“…On the contrary, small-molecule screening is an alternative way to identify inhibitors to Cho1 independent of structural information. Two whole-cell screens have been carried out to identify Cho1 inhibitors, but neither has been successful ( 45 , 46 ). One identified the compound SB-224289, but it was discovered that SB-224289 only affects Cho1-associated physiological pathways ( 45 ).…”

Section: Introductionmentioning

confidence: 99%

“…One identified the compound SB-224289, but it was discovered that SB-224289 only affects Cho1-associated physiological pathways ( 45 ). The other screen identified bleomycin, but this again impacts phospholipid-related physiologies rather than Cho1 itself ( 46 ). Thus, to carry out identification of a Cho1 inhibitor, a target-based screen was developed.…”

Section: Introductionmentioning

confidence: 99%

The small molecule CBR-5884 inhibits the Candida albicans phosphatidylserine synthase

Zhou,

Phelps,

Mangrum

et al. 2024

mBio

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Systemic infections by Candida spp. are associated with high mortality rates, partly due to limitations in current antifungals, highlighting the need for novel drugs and drug targets. The fungal phosphatidylserine synthase, Cho1, from Candida albicans is a logical antifungal drug target due to its importance in virulence, absence in the host, and conservation among fungal pathogens. Inhibitors of Cho1 could serve as lead compounds for drug development, so we developed a target-based screen for inhibitors of purified Cho1. This enzyme condenses serine and cytidyldiphosphate-diacylglycerol (CDP-DAG) into phosphatidylserine (PS) and releases cytidylmonophosphate (CMP). Accordingly, we developed an in vitro nucleotidase-coupled malachite-green-based high throughput assay for purified C. albicans Cho1 that monitors CMP production as a proxy for PS synthesis. Over 7,300 molecules curated from repurposing chemical libraries were interrogated in primary and dose-responsivity assays using this platform. The screen had a promising average Z ’ score of ~0.8, and seven compounds were identified that inhibit Cho1. Three of these, ebselen, LOC14, and CBR-5884, exhibited antifungal effects against C. albicans cells, with fungicidal inhibition by ebselen and fungistatic inhibition by LOC14 and CBR-5884. Only CBR-5884 showed evidence of disrupting in vivo Cho1 function by inducing phenotypes consistent with the cho1∆∆ mutant, including a reduction of cellular PS levels. Kinetics curves and computational docking indicate that CBR-5884 competes with serine for binding to Cho1 with a K i of 1,550 ± 245.6 nM. Thus, this compound has the potential for development into an antifungal compound. IMPORTANCE Fungal phosphatidylserine synthase (Cho1) is a logical antifungal target due to its crucial role in the virulence and viability of various fungal pathogens, and since it is absent in humans, drugs targeted at Cho1 are less likely to cause toxicity in patients. Using fungal Cho1 as a model, there have been two unsuccessful attempts to discover inhibitors for Cho1 homologs in whole-cell screens prior to this study. The compounds identified in these attempts do not act directly on the protein, resulting in the absence of known Cho1 inhibitors. The significance of our research is that we developed a high-throughput target-based assay and identified the first Cho1 inhibitor, CBR-5884, which acts both on the purified protein and its function in the cell. This molecule acts as a competitive inhibitor with a K i value of 1,550 ± 245.6 nM and, thus, has the potential for development into a new class of antifungals targeting PS synthase.

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The Anticancer Drug Bleomycin Shows Potent Antifungal Activity by Altering Phospholipid Biosynthesis

Cited by 5 publications

References 52 publications

Synthesis of Silver Nanoparticles Using Camellia sinensis Leaf Extract: Promising Particles for the Treatment of Cancer and Diabetes

Synthesis of Silver Nanoparticles Using Camellia sinensis Leaf Extract: Promising Particles for the Treatment of Cancer and Diabetes

Innovations in Antifungal Drug Discovery among Cell Envelope Synthesis Enzymes through Structural Insights

The small molecule CBR-5884 inhibits the Candida albicans phosphatidylserine synthase

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