An old activity in the cytochrome P450 superfamily (CYP51) and a new story of drugs and resistance

2001 ◽  
Vol 29 (2) ◽  
pp. 122-128 ◽  
Author(s):  
S. L. Kelly ◽  
D. C. Lamb ◽  
M. Cannieux ◽  
D. Greetham ◽  
C. J. Jackson ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Fungal Pathogens ◽  
Antifungal Drugs

Cytochrome P450 51 (CYP51) is sterol 14α-demethylase, known also as Ergllp in yeast. First studied in yeast, where it is one of three CYPs in the genome, it has subsequently gained attention as the only CYP found so far in different kingdoms of life. As such it is central to considerations of CYP evolution. Recent use of CYP51-inhibiting antifungal drugs, such as fluconazole, has also been associated with dramatic CYP51 evolution to numerous resistant forms in fungal pathogens. CYP51 has also been discovered in mycobacteria where antifungal azoles have effect and might be of value against tuberculosis. Evolutionary and therapeutic aspects of CYP51 studies are discussed.

Biosynthesis of selenium nanoparticles by Aspergillus flavus and Candida albicans and comparison of their effects with antifungal drugs

2021 ◽  
Author(s):  
Mahdi Hosseini Bafghi ◽  
Razieh Nazari ◽  
Majid Darroudi ◽  
Mohsen Zargar ◽  
Hossein Zarrinfar
Keyword(s):  
Candida Albicans ◽  
Aspergillus Flavus ◽  
Fungal Pathogens ◽  
Chemical Properties ◽  
Cost Effective ◽  
Antifungal Drugs ◽  
Selenium Nanoparticles ◽  
Fungal Strains ◽  
Vis Spectroscopy ◽  
Physical And Chemical

Abstract Biosynthesis of nanoparticles can stand as a replacement for the available chemical and physical methods by offering new procedures as green syntheses that have proved to be simple, biocompatible, safe, and cost-effective. Considering how nanoparticles with a size of 1 to 100 nanometers contain unique physical and chemical properties, recent reports are indicative of observing the antifungal qualities of selenium nanoparticles (Se-NPs). Recently, the observance of antifungal resistance towards different species of these fungi is often reported. Therefore, due to the antifungal effects of biological nanoparticles, this study aimed to investigate the exertion of these nanoparticles and evaluate their effects on the growth of fungal pathogens. Se-NPs were biosynthesized by the application of wet reduction method, which included specific concentrations of Aspergillus flavus and Candida albicans. The presence of nanoparticles was confirmed by methods such as UV-Vis spectroscopy, FT-IR analysis, and FESEM electron microscope that involved FESEM and EDAX diagram. The fungal strains were cultured in sabouraud dextrose agar medium to perform the sensitivity test based on the minimum inhibitory concentration (MIC) method in duplicate. The utilization of Se-NPs at concentrations of 1 µg/ ml and below resulted in zero growth of fungal agents. However, their growth was inhibited by antifungal drugs at concentrations of 2 µg/ ml and higher. Based on the obtained results, biological nanoparticles produced by fungal agents at different concentrations exhibited favorable inhibitory effects on the growth of fungal strains.

scholarly journals Novel Antifungal Compounds Discovered in Medicines for Malaria Venture’s Malaria Box

mSphere ◽  
2018 ◽  
Vol 3 (2) ◽  
Author(s):  
Eric H. Jung ◽  
David J. Meyers ◽  
Jürgen Bosch ◽  
Arturo Casadevall
Keyword(s):  
Candida Albicans ◽  
Antifungal Activity ◽  
Cryptococcus Neoformans ◽  
Fungal Pathogens ◽  
Pathogenic Fungi ◽  
Cryptococcus Gattii ◽  
Antifungal Drugs ◽  
Resistant Bacteria ◽  
Animal Cells ◽  
Malaria Box

ABSTRACTSimilarities in fungal and animal cells make antifungal discovery efforts more difficult than those for other classes of antimicrobial drugs. Currently, there are only three major classes of antifungal drugs used for the treatment of systemic fungal diseases: polyenes, azoles, and echinocandins. Even in situations where the offending fungal organism is susceptible to the available drugs, treatment courses can be lengthy and unsatisfactory, since eradication of infection is often very difficult, especially in individuals with impaired immunity. Consequently, there is a need for new and more effective antifungal drugs. We have identified compounds with significant antifungal activity in the Malaria Box (Medicines for Malaria Ventures, Geneva, Switzerland) that have higher efficacy than some of the currently used antifungal drugs. Our best candidate, MMV665943 (IUPAC name 4-[6-[[2-(4-aminophenyl)-3H-benzimidazol-5-yl]methyl]-1H-benzimidazol-2-yl]aniline), here referred to as DM262, showed 16- to 32-fold-higher activity than fluconazole againstCryptococcus neoformans. There was also significant antifungal activity in other fungal species with known antifungal resistance, such asLomentospora prolificansandCryptococcus gattii. Antifungal activity was also observed against a common fungus,Candida albicans. These results are important because they offer a potentially new class of antifungal drugs and the repurposing of currently available therapeutics.IMPORTANCEMuch like the recent increase in drug-resistant bacteria, there is a rise in antifungal-resistant strains of pathogenic fungi. There is a need for novel and more potent antifungal therapeutics. Consequently, we investigated a mixed library of drug-like and probe-like compounds with activity inPlasmodiumspp. for activity against two common fungal pathogens,Cryptococcus neoformansandCandida albicans, along with two less common pathogenic species,Lomentospora prolificansandCryptococcus gattii. We uncover a previously uncharacterized drug with higher broad-spectrum antifungal activity than some current treatments. Our findings may eventually lead to a compound added to the arsenal of antifungal therapeutics.

scholarly journals The importance of rapid diagnosis for multidrug-resistant Candida: an interview with Maurizio Sanguinetti

2019 ◽  
Vol 14 (12) ◽  
pp. 1011-1012
Author(s):  
Maurizio Sanguinetti
Keyword(s):  
Infectious Diseases ◽  
Fungal Pathogens ◽  
Fungal Infections ◽  
Resistance Mechanisms ◽  
Rapid Diagnosis ◽  
Antifungal Drugs ◽  
Full Professor ◽  
Research Activity ◽  
Diagnostic Strategies ◽  
Personalized Care

In this exclusive interview, Maurizio Sanguinetti discusses current issues with Candida fungal infection diagnoses, in light of its rising resistance to antifungal drugs. This interview was conducted by Ellen Colvin, Editor of Future Microbiology. Maurizio Sanguinetti, MD, is full Professor of Microbiology at the Università Cattolica del Sacro Cuore of Rome, Italy, and Director of the Institute of Microbiology and Chief of the Department of Laboratory Sciences and Infectious Diseases Sciences at the Fondazione Policlinico Agostino Gemelli IRCCS of Rome, Italy. For several years, the research activity of Maurizio Sanguinetti has mainly focused on the development of molecular methods for the rapid diagnosis of bacterial, mycobacterial and fungal infections; the elucidation of virulence and antimicrobial resistance mechanisms in clinically relevant bacterial and fungal pathogens; the characterization of the human microbiota in relationship to infectious and noninfectious diseases and implementation of new diagnostic strategies for the personalized care of patients with infectious diseases.

scholarly journals High Efficiency Drug Repurposing Design for New Antifungal Agents

2019 ◽  
Vol 2 (2) ◽  
pp. 31 ◽  
Author(s):  
Jong H. Kim ◽  
Kathleen L. Chan ◽  
Luisa W. Cheng ◽  
Lisa A. Tell ◽  
Barbara A. Byrne ◽  
...  
Keyword(s):  
Antifungal Activity ◽  
Fungal Pathogens ◽  
Antifungal Agents ◽  
High Efficiency ◽  
Intervention Strategy ◽  
Drug Repurposing ◽  
Antifungal Drugs ◽  
Antifungal Drug ◽  
Alternative Intervention ◽  
Combined Application

Current antifungal interventions have often limited efficiency in treating fungal pathogens, particularly those resistant to commercial drugs or fungicides. Antifungal drug repurposing is an alternative intervention strategy, whereby new utility of various marketed, non-antifungal drugs could be repositioned as novel antifungal agents. In this study, we investigated “chemosensitization” as a method to improve the efficiency of antifungal drug repurposing, wherein combined application of a second compound (viz., chemosensitizer) with a conventional, non-antifungal drug could greatly enhance the antifungal activity of the co-applied drug. Redox-active natural compounds or structural derivatives, such as thymol (2-isopropyl-5-methylphenol), 4-isopropyl-3-methylphenol, or 3,5-dimethoxybenzaldehyde, could serve as potent chemosensitizers to enhance antifungal activity of the repurposed drug bithionol. Of note, inclusion of fungal mutants, such as antioxidant mutants, could also facilitate drug repurposing efficiency, which is reflected in the enhancement of antifungal efficacy of bithionol. Bithionol overcame antifungal (viz., fludioxonil) tolerance of the antioxidant mutants of the human/animal pathogen Aspergillus fumigatus. Altogether, our strategy can lead to the development of a high efficiency drug repurposing design, which enhances the susceptibility of pathogens to drugs, reduces time and costs for new antifungal development, and abates drug or fungicide resistance.

Resistance to antifungal therapies

2017 ◽  
Vol 61 (1) ◽  
pp. 157-166 ◽  
Author(s):  
Rajendra Prasad ◽  
Atanu Banerjee ◽  
Abdul Haseeb Shah
Keyword(s):  
Fungal Pathogens ◽  
Molecular Mechanisms ◽  
Fungal Infections ◽  
Therapeutic Strategies ◽  
Antifungal Resistance ◽  
Antifungal Drugs ◽  
Therapeutic Interventions ◽  
Medical Professionals ◽  
Comprehensive Understanding ◽  
Novel Targets

The evolution of antifungal resistance among fungal pathogens has rendered the limited arsenal of antifungal drugs futile. Considering the recent rise in the number of nosocomial fungal infections in immunocompromised patients, the emerging clinical multidrug resistance (MDR) has become a matter of grave concern for medical professionals. Despite advances in therapeutic interventions, it has not yet been possible to devise convincing strategies to combat antifungal resistance. Comprehensive understanding of the molecular mechanisms of antifungal resistance is essential for identification of novel targets that do not promote or delay emergence of drug resistance. The present study discusses features and limitations of the currently available antifungals, mechanisms of antifungal resistance and highlights the emerging therapeutic strategies that could be deployed to combat MDR.

scholarly journals TheAspergillus fumigatusDamage Resistance Protein Family Coordinately Regulates Ergosterol Biosynthesis and Azole Susceptibility

mBio ◽  
2016 ◽  
Vol 7 (1) ◽  
Author(s):  
Jinxing Song ◽  
Pengfei Zhai ◽  
Yuanwei Zhang ◽  
Caiyun Zhang ◽  
Hong Sang ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Fungal Pathogens ◽  
Regulatory System ◽  
Ergosterol Biosynthesis ◽  
Heme Binding ◽  
Cytochrome P450 Enzymes ◽  
Azole Antifungals ◽  
Ergosterol Synthesis ◽  
Resistance Protein ◽  
Cytochrome P450 Protein

ABSTRACTErgosterol is a major and specific component of the fungal plasma membrane, and thus, the cytochrome P450 enzymes (Erg proteins) that catalyze ergosterol synthesis have been selected as valuable targets of azole antifungals. However, the opportunistic pathogenAspergillus fumigatushas developed worldwide resistance to azoles largely through mutations in the cytochrome P450 enzyme Cyp51 (Erg11). In this study, we demonstrate that a cytochromeb5-like heme-binding damage resistance protein (Dap) family, comprised of DapA, DapB, and DapC, coordinately regulates the functionality of cytochrome P450 enzymes Erg5 and Erg11 and oppositely affects susceptibility to azoles. The expression of all three genes is induced in an azole concentration-dependent way, and the decreased susceptibility to azoles requires DapA stabilization of cytochrome P450 protein activity. In contrast, overexpression of DapB and DapC causes dysfunction of Erg5 and Erg11, resulting in abnormal accumulation of sterol intermediates and further accentuating the sensitivity of ΔdapAstrains to azoles. The results of exogenous-hemin rescue and heme-binding-site mutagenesis experiments demonstrate that the heme binding of DapA contributes the decreased azole susceptibility, while DapB and -C are capable of reducing the activities of Erg5 and Erg11 through depletion of heme.In vivodata demonstrate that inactivated DapA combined with activated DapB yields anA. fumigatusmutant that is easily treatable with azoles in an immunocompromised mouse model of invasive pulmonary aspergillosis. Compared to the single Dap proteins found inSaccharomyces cerevisiaeandSchizosaccharomyces pombe, we suggest that this complex Dap family regulatory system emerged during the evolution of fungi as an adaptive means to regulate ergosterol synthesis in response to environmental stimuli.IMPORTANCEKnowledge of the ergosterol biosynthesis route in fungal pathogens is useful in the design of new antifungal drugs and could aid in the study of antifungal-drug resistance mechanisms. In this study, we demonstrate that three cytochromeb5-like Dap proteins coordinately regulate the azole resistance and ergosterol biosynthesis catalyzed by cytochrome P450 proteins. Our new insights into the Dap regulatory system in fungal pathogens may have broad therapeutic ramifications beyond their usefulness for classic azole antifungals. Moreover, our elucidation of the molecular mechanism of Dap regulation of cytochrome P450 protein functionality through heme-binding activity may extend beyond the Kingdom Fungi with applicability toward Dap protein regulation of mammalian sterol synthesis.

scholarly journals Candida Infections and Their Prevention

2013 ◽  
Vol 2013 ◽  
pp. 1-13 ◽  
Author(s):  
M. Anaul Kabir ◽  
Zulfiqar Ahmad
Keyword(s):  
Antifungal Therapy ◽  
Fungal Pathogens ◽  
Antifungal Drugs ◽  
Advanced Technology ◽  
Fast Detection ◽  
Synthetic Drugs ◽  
Clinical Level ◽  
Candida Infections ◽  
Prevention And Cure ◽  
Modern Technologies

Infections caused by Candida species have been increased dramatically worldwide due to the increase in immunocompromised patients. For the prevention and cure of candidiasis, several strategies have been adopted at clinical level. Candida infected patients are commonly treated with a variety of antifungal drugs such as fluconazole, amphotericin B, nystatin, and flucytosine. Moreover, early detection and speciation of the fungal agents will play a crucial role for administering appropriate drugs for antifungal therapy. Many modern technologies like MALDI-TOF-MS, real-time PCR, and DNA microarray are being applied for accurate and fast detection of the strains. However, during prolonged use of these drugs, many fungal pathogens become resistant and antifungal therapy suffers. In this regard, combination of two or more antifungal drugs is thought to be an alternative to counter the rising drug resistance. Also, many inhibitors of efflux pumps have been designed and tested in different models to effectively treat candidiasis. However, most of the synthetic drugs have side effects and biomedicines like antibodies and polysaccharide-peptide conjugates could be better alternatives and safe options to prevent and cure the diseases. Furthermore, availability of genome sequences of Candida  albicans and other non-albicans strains has made it feasible to analyze the genes for their roles in adherence, penetration, and establishment of diseases. Understanding the biology of Candida species by applying different modern and advanced technology will definitely help us in preventing and curing the diseases caused by fungal pathogens.

scholarly journals Chaperone Networks in Fungal Pathogens of Humans

2021 ◽  
Vol 7 (3) ◽  
pp. 209
Author(s):  
Linda C. Horianopoulos ◽  
James W. Kronstad
Keyword(s):  
Immune Response ◽  
Candida Albicans ◽  
Fungal Pathogens ◽  
Morphological Changes ◽  
Antifungal Drugs ◽  
Promising Strategy ◽  
Human Body Temperature ◽  
Small Hsps ◽  
J Domain ◽  
Shock Proteins

The heat shock proteins (HSPs) function as chaperones to facilitate proper folding and modification of proteins and are of particular importance when organisms are subjected to unfavourable conditions. The human fungal pathogens are subjected to such conditions within the context of infection as they are exposed to human body temperature as well as the host immune response. Herein, the roles of the major classes of HSPs are briefly reviewed and their known contributions in human fungal pathogens are described with a focus on Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus. The Hsp90s and Hsp70s in human fungal pathogens broadly contribute to thermotolerance, morphological changes required for virulence, and tolerance to antifungal drugs. There are also examples of J domain co-chaperones and small HSPs influencing the elaboration of virulence factors in human fungal pathogens. However, there are diverse members in these groups of chaperones and there is still much to be uncovered about their contributions to pathogenesis. These HSPs do not act in isolation, but rather they form a network with one another. Interactions between chaperones define their specific roles and enhance their protein folding capabilities. Recent efforts to characterize these HSP networks in human fungal pathogens have revealed that there are unique interactions relevant to these pathogens, particularly under stress conditions. The chaperone networks in the fungal pathogens are also emerging as key coordinators of pathogenesis and antifungal drug tolerance, suggesting that their disruption is a promising strategy for the development of antifungal therapy.

scholarly journals Effects of Cytochrome P450 Inhibitors on Itraconazole and Fluconazole Induced Cytotoxicity in Hepatocytes

2009 ◽  
Vol 2009 ◽  
pp. 1-7 ◽  
Author(s):  
Nhareet Somchit ◽  
Chong Sock Ngee ◽  
Azhar Yaakob ◽  
Zuraini Ahmad ◽  
Zainul Amiruddin Zakaria
Keyword(s):  
Cytochrome P450 ◽  
Liver Perfusion ◽  
Antifungal Drugs ◽  
Female Rats ◽  
Atp Levels ◽  
P450 Inhibitors ◽  
Hepatocyte Toxicity

Itraconazole and fluconazole have been reported to induce hepatotoxicity in patients. The present study was designed to investigate the role of cytochrome P450 inhibitors, SKF 525A, and curcumin pretreatment on the cytotoxicity of antifungal drugs fluconazole and itraconazole. For 3 consecutive days, female rats were administered daily SKF 525A or curcumin (5 and 25 mg/kg). Control rats received an equivalent amount of dosed vehicle. The animals were anaesthetized 24 hours after receiving the last dose for liver perfusion. Hepatocytes were then exposed to various concentrations of antifungal drugs. In vitro incubation of hepatocytes with itraconazole revealed significantly lower viability when compared to fluconazole as assessed by lactate dehydrogenase, aspartate aminotransferase and alanine aminotransferase activities. The cytotoxicity of itraconazole was enhanced when incubated with hepatocytes pretreated with SKF 525A. SKF 525A had no effects on the cytotoxicity of fluconazole. Curcumin failed to either increase or decrease the cytotoxicity of both antifungal drugs. ATP levels also showed significant decrease in both itraconazole and fluconazole incubated hepatocytes. However, SKF 525A pretreated hepatocytes had significantly lower ATP levels after itraconazole incubations. Collectively, these results confirm the involvement of cytochrome P450 in the cytoprotection in itraconazole induced hepatocyte toxicity. Differences of the effects of SKF 525A on the cytotoxicity induced by itraconazole and fluconazole may be due to the differences on the metabolism of each antifungal drug in vivo.

scholarly journals Architecture of a single membrane spanning cytochrome P450 suggests constraints that orient the catalytic domain relative to a bilayer

2014 ◽  
Vol 111 (10) ◽  
pp. 3865-3870 ◽  
Author(s):  
Brian C. Monk ◽  
Thomas M. Tomasiak ◽  
Mikhail V. Keniya ◽  
Franziska U. Huschmann ◽  
Joel D. A. Tyndall ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Catalytic Domain ◽  
Transmembrane Helix ◽  
Protein Structures ◽  
Antifungal Drugs ◽  
Integral Membrane Proteins ◽  
Ergosterol Biosynthesis ◽  
Amphipathic Helix ◽  
Membrane Spanning ◽  
And Function

Bitopic integral membrane proteins with a single transmembrane helix play diverse roles in catalysis, cell signaling, and morphogenesis. Complete monospanning protein structures are needed to show how interaction between the transmembrane helix and catalytic domain might influence association with the membrane and function. We report crystal structures of full-length Saccharomyces cerevisiae lanosterol 14α-demethylase, a membrane monospanning cytochrome P450 of the CYP51 family that catalyzes the first postcyclization step in ergosterol biosynthesis and is inhibited by triazole drugs. The structures reveal a well-ordered N-terminal amphipathic helix preceding a putative transmembrane helix that would constrain the catalytic domain orientation to lie partly in the lipid bilayer. The structures locate the substrate lanosterol, identify putative substrate and product channels, and reveal constrained interactions with triazole antifungal drugs that are important for drug design and understanding drug resistance.

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