scholarly journals Repurposing Benzbromarone as Antifolate to Develop Novel Antifungal Therapy for Candida Albicans

2021 ◽  
Author(s):  
Somdutt Mujwar ◽  
Avanish Tripathi
Keyword(s):  
Candida Albicans ◽  
Antifungal Therapy ◽  
Fungal Infections ◽  
Docking Simulation ◽  
Drug Repurposing ◽  
Macromolecular Complex ◽  
Novel Therapy ◽  
Agent Based ◽  
Severe Infections ◽  
Essential Enzyme

Abstract Fungal infections in humans are responsible for mild to severe infections resulting in the systemic effects responsible for a large amount of mortality. The invasive fungal infections are having similar symptomatic effects to those of COVID-19. The COVID-19 patients are immunocompromised in nature and have a high probability of developing severe fungal infections resulting in the development of further complications. The existing antifungal therapy is having associated problems related to the development of drug resistance, sub-potent in nature, and the presence of undesirable toxic effects. The fungal dihydrofolate reductase is an essential enzyme involved in the absorption of dietary folic acid and its conversion into tetrahydrofolate, which is a coenzyme required for the biosynthesis of the fungal nucleotides. Thus, in the current study, an attempt has been made to identify potential folate inhibitors of Candida albicans by a computational drug repurposing approach. Benzbromarone is identified as a potential anti-folate agent based upon the molecular docking simulation-based virtual screening followed by the molecular dynamic simulation of the macromolecular complex for the development of a novel therapy for the treatment of candidiasis.

Primary Prophylaxis against Invasive Fungal Infections (IFI) with Posaconazole (POS) or Voriconazole (VRC) Shows Better Efficacy Compared to No Systemic Prophylaxis during Induction and Consolidation Chemotherapy Cycles of Adult Acute Leukemia Patients

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4834-4834
Author(s):  
Mario E Ojeda Uribe ◽  
Catherine Berg ◽  
Alain Gravet ◽  
Eric Sauleau ◽  
Dominique Bourderont ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Antifungal Therapy ◽  
De Novo ◽  
Fungal Infections ◽  
Primary Prophylaxis ◽  
Candida Krusei ◽  
Significant Difference ◽  
Empirical Antifungal Therapy ◽  
Aspergillus Sp ◽  
Group B

Abstract IFI are a well-known cause of severe morbidity and mortality in leukemic patients with chemotherapy induced neutropenia. From 2007 to date, during the induction and consolidation cycles of either de novo or relapsed adult leukemic patients we have administered a primary prophylaxis against IFI with the azole agents POS or VRC. This was compared to a two-year historical control without systemic primary prophylaxis. The whole population (mean age 51.3 yrs; n male =94; n female =43) included ALL patients (n cycles=33); AML (n cycles=88); transformed AREB-2 (n cycles=9); transformed CML (n cycles=7). Most of the chemotherapy regimens administered were those used by clinical trials of the GOELAMS and GRAALL French cooperative groups. Three periods were compared: 2005–2006 where no systemic primary prophylaxis was administered (n=63; mean age 47.2 yrs), the principal agent used was amphotericine B deoxycholate in oral suspension, 1000 mg (10 ml) thrice a day); January to September 2007 where VRC was administered either orally or intravenously 200 mg bid (n=23; mean age 51.1 yrs) and October 2007 to date where POS was administered orally at the standard dose of 200 mg (5ml) thrice a day (n=50; mean age 56 yrs). POS patients were significantly older (p<0.02) because of the present trend to treat most of the elderly patients as they are considered fit to receive chemotherapy. Prophylaxis was administered since the start of the chemotherapy until neutrophil recovery (PNN count ≥1×109/L for at least 3 days). Most patients received daily G-CSF (lenogastrim, 263 mg/day) from the end of chemotherapy and most of them were placed in laminar airflow rooms. The incidence of IFI until 60 days post-chemotherapy (EORTC criteria) was significantly higher in group A compared to either group B or C (p=0.007) or compared to both groups together (p=0.002). IFI-A: 15/63 (10 proven: 1 aspergillus fumigatus, 1 candida krusei, 4 candida albicans, 3 candida glabrata, 1 candida tropicalis; 5 probable: 5 aspergillus sp); IFI-B: 1/23 (1 proven: 1 candida lusitaniae) IFI-C: 3/50 (2 proven: 1 candida krusei, 1 candida albicans) (1 probable: 1 aspergillus sp). No significant difference was found on the IFI incidence between groups B and C. Diagnosis or type of chemotherapy did not show any significant difference on the incidence of IFI. However, patients in first relapse, refractory or CR2 had a significant higher incidence of IFI (p = 0.03) compared to first time induction or consolidation cycles for RC1 patients. All the IFI in the POS group were observed in relapsed (n=2) or refractory patients (n=1), as it was the case of IFI in a refractory patient of the VRC group. Moreover, empirical antifungal therapy was most frequently administered in relapsed or refractory patients (p=0.03) compared to de novo or CR1 patients. Although most of the IFI were observed during the induction cycles (n=16), no significant difference was found with the consolidation cycles (n=3). Group C received more empirical antifungal therapy (18%) compared to 9.5% in the group B, without a significant difference. In conclusion, primary phrophylaxis with azole agents, either POS or VRC has had a significant impact to decrease the incidence of IFI in our population of leukemic patients. This prophylaxis appears to be even more critical in relapsed or refractory patients, who exhibit a higher risk of IFI. Moreover, preliminary cost-effectiveness analysis appears to be in favour of this therapeutic option.

scholarly journals Computational Drug Repurposing Resources and Approaches for Discovering Novel Antifungal Drugs against Candida albicans N-Myristoyl Transferase

2021 ◽  
Author(s):  
Afzal Hussain ◽  
Chandan Kumar Verma
Keyword(s):  
Candida Albicans ◽  
Fungal Infections ◽  
Drug Repurposing ◽  
Time Frame ◽  
Pharmacophore Modeling ◽  
Antifungal Drugs ◽  
Low Birth Weight Infants ◽  
Drug Candidates ◽  
Opportunistic Fungal Pathogen ◽  
Chemotherapy Patients

Candida albicans is a yeast that is an opportunistic fungal pathogen and also identified as ubiquitous polymorphic species that is mainly linked with major fungal infections in humans, particularly in the immunocompromised patients including transplant recipients, chemotherapy patients, HIV-infected patients as well as in low-birth-weight infants. Systemic Candida infections have a high mortality rate of around 29 to 76%. For reducing its infection, limited drugs are existing such as caspofungin, fluconazole, terbinafine, and amphotericin B, etc. which contain unlikable side effects and also toxic. This review intends to utilize advanced bioinformatics technologies such as Molecular docking, Scaffold hopping, Virtual screening, Pharmacophore modeling, Molecular dynamics (MD) simulation for the development of potentially new drug candidates with a drug-repurpose approach against Candida albicans within a limited time frame and also cost reductive.

Ultrastructural Changes of Candida albicans Species Induced by the Presence of Sodium Diclofenac

2017 ◽  
Vol 68 (11) ◽  
pp. 2566-2569 ◽  
Author(s):  
Elena Rusu ◽  
Ionela Sarbu ◽  
Magdalena Mitache ◽  
Horatiu Moldovan ◽  
Carmen Ioana Biris ◽  
...  
Keyword(s):  
Candida Albicans ◽  
High Frequency ◽  
Fungal Infections ◽  
Diagnostic Methods ◽  
Ultrastructural Changes ◽  
Frequency Of Occurrence ◽  
Medical Treatments ◽  
Sodium Diclofenac ◽  
Cell Wall Disruption ◽  
Candidiasis Treatment

The high frequency of occurrence of candidiasis as well as high mortality of patients with immunosuppression cause a tendency toward better understanding of Candida albicans species virulence factors and developing sensitive and specific diagnostic methods, and appropriate strategies of candidiasis treatment. In recent decades the incidence of fungal infections has alarming increases because of advanced medical treatments. In this study was analyzed possible ultrastructural changes of the species C. albicans cells following treatment with sodium diclofenac at various concentrations. Following treatment of C. albicans cells with sodium diclofenac 1 mM and 2 mM changes in the plasmalemma can be noticed, changes in the density of cell wall, disruption and necrotic appearance of the cytoplasm.

The Importance of Fluconazole in Treatment of Endogenous Endophtalmitis in Patients Prior Treated Using Negative Pressure Therapy for Wound Closure Contaminated with Meticillin-resistant Staphylococcus aureus

2017 ◽  
Vol 68 (7) ◽  
pp. 1598-1601 ◽  
Author(s):  
Anisia Iuliana Alexa ◽  
Roxana Ciuntu ◽  
Alina Cantemir ◽  
Nicoleta Anton ◽  
Ciprian Danielescu ◽  
...  
Keyword(s):  
Antifungal Agents ◽  
Fungal Infections ◽  
Prolonged Treatment ◽  
Endogenous Endophthalmitis ◽  
Pressure Therapy ◽  
First Case ◽  
Severe Infections ◽  
Pars Plana ◽  
Delay In Treatment ◽  
Vitreous Biopsy

Severe infections with C. albicans should be treated promptly with antifungal agents, any delay in treatment increases the risk of endophthalmitis. The systemic Amphotericin B therapy is the gold standard in the treatment of endophthalmitis, but in the case of fungal infections it has not yet been determined. Numerous studies have shown that the use of Fluconazole is effective in the treatment of fungal endophthalmitis. In this paper, we report two cases (3 eyes) that have been presented for the same accusations of significant decrease of AV (visual acuity), ocular pain and blepharospasm suddenly installed, both of which required urgent antibiotic and intravenous antifungal treatment. Both are diagnosed with endogenous endophthalmitis and vitreous biopsy + VPP (pars plana vitrectomy) are performed, with a negative result of the vitreous culture. In both situations the treatment was with antibiotic and systemic antifungals. Postoperatively, evolution was favorable in the first case and less favorable in the second one. The prognosis depends on the virulence of the microorganisms and the time elapsed until initiation of the treatment. Also, the presence of risk factors such as diabetes, sepsis, recent abdominal surgery (C. Albicans is part of the comesary flora of the digestive tract) have influenced the prognosis decisively. Severe infections with C. albicans should be promptly treated with antifungal agents, any delay in treatment increases the risk of endophthalmitis. Even when prolonged treatment of candidemia is instituted, 3% of patients can develop endogenous endophthalmitis, so ocular evaluation is particularly important for patients immobilized in anesthesia and intensive care units.

Efficacy of Novel Schiff base Derivatives as Antifungal Compounds in Combination with Approved Drugs Against Candida Albicans

2019 ◽  
Vol 15 (6) ◽  
pp. 648-658 ◽  
Author(s):  
Manzoor Ahmad Malik ◽  
Shabir Ahmad Lone ◽  
Parveez Gull ◽  
Ovas Ahmad Dar ◽  
Mohmmad Younus Wani ◽  
...  
Keyword(s):  
Schiff Base ◽  
Candida Albicans ◽  
Antifungal Activity ◽  
Fungal Infections ◽  
Total Sterol ◽  
Antifungal Drugs ◽  
New Drugs ◽  
Ergosterol Biosynthesis ◽  
Dependent Manner ◽  
Schiff Base Derivatives

Background: The increasing incidence of fungal infections, especially caused by Candida albicans, and their increasing drug resistance has drastically increased in recent years. Therefore, not only new drugs but also alternative treatment strategies are promptly required. Methods: We previously reported on the synergistic interaction of some azole and non-azole compounds with fluconazole for combination antifungal therapy. In this study, we synthesized some non-azole Schiff-base derivatives and evaluated their antifungal activity profile alone and in combination with the most commonly used antifungal drugs- fluconazole (FLC) and amphotericin B (AmB) against four drug susceptible, three FLC resistant and three AmB resistant clinically isolated Candida albicans strains. To further analyze the mechanism of antifungal action of these compounds, we quantified total sterol contents in FLC-susceptible and resistant C. albicans isolates. Results: A pyrimidine ring-containing derivative SB5 showed the most potent antifungal activity against all the tested strains. After combining these compounds with FLC and AmB, 76% combinations were either synergistic or additive while as the rest of the combinations were indifferent. Interestingly, none of the combinations was antagonistic, either with FLC or AmB. Results interpreted from fractional inhibitory concentration index (FICI) and isobolograms revealed 4-10-fold reduction in MIC values for synergistic combinations. These compounds also inhibit ergosterol biosynthesis in a concentration-dependent manner, supported by the results from docking studies. Conclusion: The results of the studies conducted advocate the potential of these compounds as new antifungal drugs. However, further studies are required to understand the other mechanisms and in vivo efficacy and toxicity of these compounds.

scholarly journals CD137 Signaling Is Critical in Fungal Clearance during Systemic Candida albicans Infection

2021 ◽  
Vol 7 (5) ◽  
pp. 382
Author(s):  
Vuvi G. Tran ◽  
Na N. Z. Nguyen ◽  
Byungsuk Kwon
Keyword(s):  
Candida Albicans ◽  
Defense Mechanisms ◽  
Tumor Necrosis ◽  
Fungal Infections ◽  
Fungal Growth ◽  
Wild Type ◽  
Agonistic Antibody ◽  
Innate Defense ◽  
Surface Receptor ◽  
Candida Albicans Infection

Invasive fungal infections by Candida albicans frequently cause mortality in immunocompromised patients. Neutrophils are particularly important for fungal clearance during systemic C. albican infection, yet little has been known regarding which surface receptor controls neutrophils’ antifungal activities. CD137, which is encoded by Tnfrsf9, belongs to the tumor necrosis receptor superfamily and has been shown to regulate neutrophils in Gram-positive bacterial infection. Here, we used genetic and immunological tools to probe the involvement of neutrophil CD137 signaling in innate defense mechanisms against systemic C. albicans infection. We first found that Tnfrsf9−/− mice were susceptible to C. albicans infection, whereas injection of anti-CD137 agonistic antibody protected the host from infection, suggesting that CD137 signaling is indispensable for innate immunity against C. albicans infection. Priming of isolated neutrophils with anti-CD137 antibody promoted their phagocytic and fungicidal activities through phospholipase C. In addition, injection of anti-CD137 antibody significantly augmented restriction of fungal growth in Tnfrsf9−/− mice that received wild-type (WT) neutrophils. In conclusion, our results demonstrate that CD137 signaling contributes to defense mechanisms against systemic C. albicans infection by promoting rapid fungal clearance.

scholarly journals Eap1p, an Adhesin That Mediates Candida albicans Biofilm Formation In Vitro and In Vivo

2007 ◽  
Vol 6 (6) ◽  
pp. 931-939 ◽  
Author(s):  
Fang Li ◽  
Michael J. Svarovsky ◽  
Amy J. Karlsson ◽  
Joel P. Wagner ◽  
Karen Marchillo ◽  
...  
Keyword(s):  
Candida Albicans ◽  
Cell Adhesion ◽  
Biofilm Formation ◽  
Fungal Infections ◽  
Gene Dosage ◽  
Venous Catheter ◽  
Flow Chamber ◽  
Dependent Manner

ABSTRACT Candida albicans is the leading cause of systemic fungal infections in immunocompromised humans. The ability to form biofilms on surfaces in the host or on implanted medical devices enhances C. albicans virulence, leading to antimicrobial resistance and providing a reservoir for infection. Biofilm formation is a complex multicellular process consisting of cell adhesion, cell growth, morphogenic switching between yeast form and filamentous states, and quorum sensing. Here we describe the role of the C. albicans EAP1 gene, which encodes a glycosylphosphatidylinositol-anchored, glucan-cross-linked cell wall protein, in adhesion and biofilm formation in vitro and in vivo. Deleting EAP1 reduced cell adhesion to polystyrene and epithelial cells in a gene dosage-dependent manner. Furthermore, EAP1 expression was required for C. albicans biofilm formation in an in vitro parallel plate flow chamber model and in an in vivo rat central venous catheter model. EAP1 expression was upregulated in biofilm-associated cells in vitro and in vivo. Our results illustrate an association between Eap1p-mediated adhesion and biofilm formation in vitro and in vivo.

scholarly journals Molecular Insights into the Fungus-Specific Serine/Threonine Protein Phosphatase Z1 in Candida albicans

mBio ◽  
2016 ◽  
Vol 7 (4) ◽  
Author(s):  
Emily Chen ◽  
Meng S. Choy ◽  
Katalin Petrényi ◽  
Zoltán Kónya ◽  
Ferenc Erdődi ◽  
...  
Keyword(s):  
Candida Albicans ◽  
High Mortality ◽  
Protein Phosphatase ◽  
Cyclic Peptide ◽  
Fungal Infections ◽  
The United States ◽  
Mortality Rates ◽  
Regulatory Proteins ◽  
Structural Elements ◽  
Novel Targets

ABSTRACT The opportunistic pathogen Candida is one of the most common causes of nosocomial bloodstream infections. Because candidemia is associated with high mortality rates and because the incidences of multidrug-resistant Candida are increasing, efforts to identify novel targets for the development of potent antifungals are warranted. Here, we describe the structure and function of the first member of a family of protein phosphatases that is specific to fungi, protein phosphatase Z1 (PPZ1) from Candida albicans . We show that PPZ1 not only is active but also is as susceptible to inhibition by the cyclic peptide inhibitor microcystin-LR as its most similar human homolog, protein phosphatase 1α (PP1α [GLC7 in the yeast Saccharomyces cerevisiae ]). Unexpectedly, we also discovered that, despite its 66% sequence identity to PP1α, the catalytic domain of PPZ1 contains novel structural elements that are not present in PP1α. We then used activity and pulldown assays to show that these structural differences block a large subset of PP1/GLC7 regulatory proteins from effectively binding PPZ1, demonstrating that PPZ1 does not compete with GLC7 for its regulatory proteins. Equally important, these unique structural elements provide new pockets suitable for the development of PPZ1-specific inhibitors. Together, these studies not only reveal why PPZ1 does not negatively impact GLC7 activity in vivo but also demonstrate that the family of fungus-specific phosphatases—especially PPZ1 from C. albicans —are highly suitable targets for the development of novel drugs that specifically target C. albicans without cross-reacting with human phosphatases. IMPORTANCE Candida albicans is a medically important human pathogen that is the most common cause of fungal infections in humans. In particular, approximately 46,000 cases of health care-associated candidiasis occur each year in the United States. Because these infections are associated with high mortality rates and because multiple species of Candida are becoming increasingly resistant to antifungals, there are increasing efforts to identify novel targets that are essential for C. albicans virulence. Here we use structural and biochemical approaches to elucidate how a member of a fungus-specific family of enzymes, serine/threonine phosphatase PPZ1, functions in C. albicans . We discovered multiple unique features of PPZ1 that explain why it does not cross-react with, and in turn compete for, PP1-specific regulators, a long-standing question in the field. Most importantly, however, these unique features identified PPZ1 as a potential target for the development of novel antifungal therapeutics that will provide new, safe, and potent treatments for candidiasis in humans.

GRYBELINĖS INFEKCIJOS INTENSYVIOSIOS TERAPIJOS SKYRIUJE

2021 ◽  
Vol 31 (1) ◽  
pp. 15-18
Author(s):  
Martynas Zaremba ◽  
Vykinta Zeleckytė ◽  
Valdonė Ališkevičiūtė
Keyword(s):  
Candida Albicans ◽  
Intensive Care ◽  
Intensive Care Units ◽  
Fungal Infections

Grybelinės infekcijos vis dažniau diagnozuojamos intensyviosios terapijos skyriuose ir tampa viena iš dažniausių sunkios būklės pacientų mirties priežasčių. Manoma, jog grybelinės infekcijos riziką didina netinkamai taikoma antibiotikoterapija, didelis imunosupresinių pacientų kiekis ir jiems atliekamos sudėtingos intervencinės procedūros. Didžioji dalis grybelinių infekcijų yra sukelta Candida genties grybelių, dažniausiai – Candida albicans. EPIC II 2007 metais atliktame tyrime 1265 pacientams iš 75 šalių buvo rasta, jog 19 proc. patogenų intensyviosios terapijos skyriuose sudarė grybeliai. Dažniausia gentis – Candida bei Aspergillus. Darbo tikslas – apžvelgti dažniausiai pasitaikančias grybelines infekcijas intensyviosios terapijos skyriuose, jų diagnostiką bei gydymą, atsižvelgiant į publikuotus mokslinius šaltinius. Literatūros šaltinių paieška buvo vykdoma tarptautinėse medicinos duomenų bazėse PubMed, UpToDate, Medscape. Į sisteminę apžvalgą įtraukti anglų kalba 2010–2020 m. publikuoti atsitiktinių imčių kontroliuojami tyrimai, originalūs stebėjimo tyrimai, atvejų ataskaitos, atvejų serijos ir apžvalgos pagal raktinius žodžius ir jų derinius: fungal infections, fungal infections in the intensive care units (ICU), fungal infections diagnostics and treatment. Mokslinių leidinių analizės rezultatai parodė grybelinės infekcijos intensyviosios terapijos skyriuose dažnėjimą, nes dėl radikalaus gydymo bei invazinių procedūrų daugėja imunosupresiškų pacientų. Dažniausia grybelinės infekcijos diagnostikos priemonė yra pasėlis. Grybelinės infekcijos gydymas priklauso nuo specifinio sukėlėjo. Dažniausiai vartojamos vaistų grupės yra azolai bei polienai.

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