Pathogenesis of Fungal Infections and Drug-Resistance Phenomenon

2020 ◽  
pp. 323-347
Author(s):  
Sudhakar Pola ◽  
Akella Vijayaramya ◽  
Pavani Sanapala ◽  
V. A. Iswarya Deepthi
Keyword(s):  
Drug Resistance ◽  
Fungal Infections

Anti-Candida activity of existing antibiotics and their derivatives when used alone or in combination with antifungals

2019 ◽  
Vol 14 (10) ◽  
pp. 899-915 ◽  
Author(s):  
Yaxin Liu ◽  
Weixin Wang ◽  
Haiying Yan ◽  
Decai Wang ◽  
Min Zhang ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Fungal Infections ◽  
Therapeutic Strategies ◽  
Candida Infection ◽  
Immunocompromised Patients ◽  
Derivatives Of

Fungal infections are a growing challenge in immunocompromised patients, especially candidiasis. The prolonged use of traditional antifungals to treat Candida infection has caused the emergence of drug resistance, especially fluconazole. Therefore, new therapeutic strategies for Candida infection are warranted. Recently, attention has been paid to the anti- Candida activity of antibiotics and their derivatives. Studies revealed that a series of antibiotics/derivatives displayed potential anti- Candida activity and some of them could significantly increase the susceptibility of antifungals. Interestingly, the derivatives of aminoglycosides were even more active than fluconazole/itraconazole/posaconazole. This article reviews the anti- Candida activities and mechanisms of antibiotics/derivatives used alone or in combination with antifungals. This review will helpfully provide novel insights for overcoming Candida resistance and discovering new antifungals.

scholarly journals Dehydrozingerone Exhibits Synergistic Antifungal Activities in Combination with Dodecanol against Budding Yeast via the Restriction of Multidrug Resistance

2018 ◽  
Vol 5 (02) ◽  
pp. e61-e67
Author(s):  
Chika Yamawaki ◽  
Yoshihiro Yamaguchi ◽  
Akira Ogita ◽  
Toshio Tanaka ◽  
Ken-ichi Fujita
Keyword(s):  
Drug Resistance ◽  
Antifungal Activity ◽  
Efflux Pump ◽  
Fungal Infections ◽  
Zingiber Officinale ◽  
Multidrug Efflux ◽  
Multidrug Efflux Pump ◽  
Yeast Saccharomyces Cerevisiae ◽  
Multidrug Transporters ◽  
Multidrug Efflux Pumps

AbstractDrug resistance in fungal infections has been a more frequent occurrence with the increasing number of immunocompromised patients. In efforts to overcome the problem of fungal drug resistance, we focused on the phenolic compound dehydrozingerone, which is isolated from Zingiber officinale. The effectiveness of this compound on the model yeast Saccharomyces cerevisiae has not been reported. In our study, dehydrozingerone showed a weak antifungal activity against the yeast, but demonstrated a synergistic effect in combination with dodecanol, which typically only restricts cell growth transiently. Efflux of rhodamine 6G through the multidrug efflux pumps was significantly restricted by dehydrozingerone. The transcription level of PDR5, encoding a primary multidrug efflux pump in S. cerevisiae, was enhanced with dodecanol treatment, whereas the level was reduced by dehydrozingerone. These results suggest that dehydrozingerone may be effective for potentiating antifungal activity of other drugs that are expelled from fungi by multidrug transporters like Pdr5p.

scholarly journals COVID-19: CRISPR/Cas-like System of nsp3 Promotes the Mutant Recombination and Drug Resistance

2021 ◽  
Author(s):  
liu wenzhong ◽  
Li hualan
Keyword(s):  
Drug Resistance ◽  
Fungal Infections ◽  
Fungal Spores ◽  
Virus Genome ◽  
Virus Protein ◽  
Coding Region ◽  
Conserved Domains ◽  
Negative Strand ◽  
Bacteria And Fungi ◽  
Novel Coronavirus

<p>Patients with novel coronavirus pneumonia usually suffer from bacterial and fungal infections, and the drug resistance problem caused by the pandemic is becoming more and more serious. Simultaneously, the SARS-COV-2 virus has a rapid mutation phenomenon, and somegene coding regions by mutation and recombination may be related to the drug resistance of the virus. Therefore, studying the relationship between the co-infection of bacteria and fungi and the evolution of SARS-COV-2 has important guiding significance for preventing a pandemic. We found that the SARS-COV-2 virus's nsp3 protein had a CRISPR/Cas 9 (II-B)-like function by searching for conserved domains. The system could target and edit the negative-strand RNA of SARS-COV-2. We speculated that the crRNA (CRISPR RNA) produced by the CRISPR/Cas system of Pseudomonas aeruginosa carried the genetic information of the conserved domains of bacteriophages and Pseudomonas, including drug resistance. After the phage lysed the Pseudomonas, the crRNA was released and attached to the fungal spores, and then invaded the patient's cells along with the spores or hyphae. nsp3 synthesized and assembled 4Fe-4S, iron-containing molecules bound to the cas4 domain, in the mitochondria of phagocytes. The iron came from hemoglobin attacked by the SARS-COV-2 virus protein. The nsp3 protein bound the crRNA in the phagocytic cytoplasm. It targeted the negative-strand RNA of SARS-COV-2, inserting conserved domain gene fragments into the negative-strand RNA through editing and splicing. Since the Cas protein had no codon checking function, the cutting and splicing would destroy the protein-coding information in the original RNA coding region, causing mutation and recombination of the SARS-COV-2 virus genome. If crRNA carried the drug resistance gene fragments of bacteria or phage, SARS-COV-2 would have similar drug resistance. Because of the growing problem of drug resistance in COVID-19 patients, we should pay attention to preventing fungi and bacteria co-infection. Avoid the CRISPR/Cas-like system of the novel coronavirus to cause rapid mutation and recombination and increased the drug resistance problem of SARS-COV-2.</p>

scholarly journals COVID-19: CRISPR/Cas-like System of nsp3 Promotes the Mutant Recombination and Drug Resistance

2021 ◽  
Author(s):  
liu wenzhong ◽  
Li hualan
Keyword(s):  
Drug Resistance ◽  
Fungal Infections ◽  
Fungal Spores ◽  
Virus Genome ◽  
Virus Protein ◽  
Coding Region ◽  
Conserved Domains ◽  
Negative Strand ◽  
Bacteria And Fungi ◽  
Novel Coronavirus

<p>Patients with novel coronavirus pneumonia usually suffer from bacterial and fungal infections, and the drug resistance problem caused by the pandemic is becoming more and more serious. Simultaneously, the SARS-COV-2 virus has a rapid mutation phenomenon, and somegene coding regions by mutation and recombination may be related to the drug resistance of the virus. Therefore, studying the relationship between the co-infection of bacteria and fungi and the evolution of SARS-COV-2 has important guiding significance for preventing a pandemic. We found that the SARS-COV-2 virus's nsp3 protein had a CRISPR/Cas 9 (II-B)-like function by searching for conserved domains. The system could target and edit the negative-strand RNA of SARS-COV-2. We speculated that the crRNA (CRISPR RNA) produced by the CRISPR/Cas system of Pseudomonas aeruginosa carried the genetic information of the conserved domains of bacteriophages and Pseudomonas, including drug resistance. After the phage lysed the Pseudomonas, the crRNA was released and attached to the fungal spores, and then invaded the patient's cells along with the spores or hyphae. nsp3 synthesized and assembled 4Fe-4S, iron-containing molecules bound to the cas4 domain, in the mitochondria of phagocytes. The iron came from hemoglobin attacked by the SARS-COV-2 virus protein. The nsp3 protein bound the crRNA in the phagocytic cytoplasm. It targeted the negative-strand RNA of SARS-COV-2, inserting conserved domain gene fragments into the negative-strand RNA through editing and splicing. Since the Cas protein had no codon checking function, the cutting and splicing would destroy the protein-coding information in the original RNA coding region, causing mutation and recombination of the SARS-COV-2 virus genome. If crRNA carried the drug resistance gene fragments of bacteria or phage, SARS-COV-2 would have similar drug resistance. Because of the growing problem of drug resistance in COVID-19 patients, we should pay attention to preventing fungi and bacteria co-infection. Avoid the CRISPR/Cas-like system of the novel coronavirus to cause rapid mutation and recombination and increased the drug resistance problem of SARS-COV-2.</p>

Targeting stress response pathways with alternative strategies as a novel antifungal approach

2021 ◽  
Vol 21 ◽  
Author(s):  
Sonam Ruhil ◽  
Vikash Kumar ◽  
Meenakshi Balhara ◽  
Monika Malik ◽  
Anil K. Chhillar
Keyword(s):  
Drug Resistance ◽  
Fungal Infections ◽  
Essential Gene ◽  
Fungal Growth ◽  
High Morbidity ◽  
Invasive Infection ◽  
Alternative Strategies ◽  
Antifungal Drug Resistance ◽  
Novel Approach ◽  
Stress Pathway

: Fungi are recognized as key pathogens in immunocompromised patients. The invasive infection always remains a problem for clinician due to high morbidity and mortality. The treatments of fungal infections are hampered by conventional drugs which are associated with resistance. Drug resistance has become an important problem in a variety of infectious diseases. The rise in the incidence of fungal infections and drug resistance has intensified the need for alternate therapies that affect a new target. This new target must be a growth essential gene product like stress pathway. It has been found that stress pathways can be a potential target in opportunistic fungal infection which played important role in virulence of pathogens. It was helpful in protection from host defense, normal fungal growth and antifungal drug resistance. The disruption of pathway using alternative strategies (chemosensitization and photo-dynamics therapy) can be a novel approach in fighting fungal infections and for drug design.

scholarly journals Construction of antifungal dual-target (SE, CYP51) pharmacophore models and the discovery of novel antifungal inhibitors

RSC Advances ◽  
2019 ◽  
Vol 9 (45) ◽  
pp. 26302-26314 ◽  
Author(s):  
Yue Dong ◽  
Min Liu ◽  
Jian Wang ◽  
Zhuang Ding ◽  
Bin Sun
Keyword(s):  
Drug Resistance ◽  
Fungal Infections ◽  
External Environment ◽  
Pharmacophore Models ◽  
Dual Target

Fungal infections and drug-resistance are rapidly increasing with the deterioration of the external environment.

scholarly journals Prevalence and Therapeutic Challenges of Fungal Drug Resistance: Role for Plants in Drug Discovery

Antibiotics ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 150 ◽  
Author(s):  
Lewis Marquez ◽  
Cassandra L. Quave
Keyword(s):  
United States ◽  
Drug Resistance ◽  
Fungal Pathogens ◽  
Fungal Infections ◽  
The United States ◽  
Multidrug Resistant ◽  
Modern Medicine ◽  
Candida Auris ◽  
Medical Ethnobotany ◽  
Global Issue

Antimicrobial resistance is a global issue that threatens the effective practice of modern medicine and global health. The emergence of multidrug-resistant (MDR) fungal strains of Candida auris and azole-resistant Aspergillus fumigatus were highlighted in the Centers for Disease Control and Prevention’s (CDC) 2019 report, Antibiotic Resistance Threats in the United States. Conventional antifungals used to treat fungal infections are no longer as effective, leading to increased mortality. Compounding this issue, there are very few new antifungals currently in development. Plants from traditional medicine represent one possible research path to addressing the issue of MDR fungal pathogens. In this commentary piece, we discuss how medical ethnobotany—the study of how people use plants in medicine—can be used as a guide to identify plant species for the discovery and development of novel antifungal therapies.

Progress and prospects for targeting Hsp90 to treat fungal infections

Parasitology ◽  
2014 ◽  
Vol 141 (9) ◽  
pp. 1127-1137 ◽  
Author(s):  
AMANDA VERI ◽  
LEAH E. COWEN
Keyword(s):  
Drug Resistance ◽  
Anticancer Agents ◽  
Fungal Pathogens ◽  
Fungal Infections ◽  
Antifungal Drugs ◽  
Effective Combination ◽  
New Strategy ◽  
Life Threatening ◽  
Hsp90 Chaperone ◽  
Hsp90 Function

SummaryFungal pathogens pose a major threat to human health worldwide. They infect billions of people each year, leading to at least 1·5 million deaths. Treatment of fungal infections is difficult due to the limited number of clinically useful antifungal drugs, and the emergence of drug resistance. A promising new strategy to enhance the efficacy of antifungal drugs and block the evolution of drug resistance is to target the molecular chaperone Hsp90. Pharmacological inhibitors of Hsp90 function that are in development as anticancer agents have potential to be repurposed as agents for combination antifungal therapy for some applications, such as biofilm infections. For systemic infections, however, effective combination therapy regimens may require Hsp90 inhibitors that can selectively target Hsp90 in the pathogen, or alternate strategies to compromise function of the Hsp90 chaperone machine. Selectively impairing Hsp90 function in the pathogen could in principle be achieved by targeting Hsp90 co-chaperones or regulators of Hsp90 function that are more divergent between pathogen and host than Hsp90. Antifungal combination therapies could also exploit downstream effectors of Hsp90 that are critical for fungal drug resistance and virulence. Here, we discuss the progress and prospects for establishing Hsp90 as an important therapeutic target for life-threatening fungal infections.

scholarly journals Pilot Study of Decitabine and Vorinostat with Chemotherapy for Relapsed ALL: A Report from the Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) Consortium

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2781-2781 ◽  
Author(s):  
Michael J. Burke ◽  
Patrick Brown ◽  
Richard Sposto ◽  
Lia Gore ◽  
Alan S. Wayne
Keyword(s):  
Drug Resistance ◽  
Research Funding ◽  
Blood Count ◽  
Histone Deacetylase Inhibitors ◽  
Fungal Infections ◽  
Complete Response ◽  
Intensive Chemotherapy ◽  
Acquired Drug Resistance ◽  
Support Research ◽  
Count Recovery

Abstract Acquired drug resistance is a major reason for relapse and death in acute lymphoblastic leukemia (ALL). Improving outcomes by targeting mechanisms of acquired drug resistance is a potential solution. DNA methyltransferase inhibitors (DNMTi) and histone deacetylase inhibitors (HDACi) have been shown to reverse drug resistance gene signatures and restore chemosensitivity in relapsed ALL. We report results investigating decitabine (DNMTi) (10-15 mg/m2/dose) and vorinostat (HDACi) (180 mg/m2/dose) with vincristine, dexamethasone, mitoxantrone and PEG-asparaginase (UKALL R3 backbone) for relapsed/refractory ALL. Twenty-three patients with refractory or ≥2nd relapse B-ALL were enrolled (Table 1). Median age was 12 (range, 1-21) years. Toxicity was graded according to CTCAE v4.0. The most common grade (Gr) 3-4 toxicities included hypokalemia (65%), anemia (61%), febrile neutropenia (57%), hypophosphatemia (43%), hyperbilirubinemia (39%), thrombocytopenia (39%), neutropenia (35%), sepsis (30%), lung infection (30%) and infection/infestations-other (30%). Non-hematologic dose limiting toxicity (DLT) was defined as any Gr 3 or 4 adverse event that was at least possibly attributed to decitabine and/or vorinostat with the exception of nausea (Gr 3), vomiting (Gr 3), transaminase elevation that returned to Gr ≤1 or baseline prior to the end of the course, fatigue, fever/infection, electrolyte abnormalities that were transient and not associated with clinical sequelae, albumin, alkaline phosphatase, GGT and anorexia. Hematologic DLT was defined as an absence of peripheral blood count recovery within 6 weeks of starting chemotherapy. Any patient who experienced a DLT after receiving at least 1 dose of decitabine or vorinostat was evaluable for DLT. Patients who did not experience a DLT had to receive a pre-determined amount of protocol therapy as outlined in the study to be evaluable for DLT. Seventeen of 23 patients were evaluable for DLT. Three patients experienced DLTs as follows: Gr 3 cholestasis, Gr 3 steatosis, Gr 4 hyperbilirubinemia (n=1); Gr 4 seizure, Gr 4 somnolence, Gr 3 delirium (n=1); and Gr 3 pneumonitis, Gr 3 hypoxia, Gr 3 hyperbilirubinemia (n=1). The study was suspended and amended after the first 5 patients enrolled (decitabine, 15mg/m2), due to significant infectious toxicities [4 of 5 patients reporting invasive fungal infections: C. kruseii (n=2), C. lusitaniae (n=1), and C. guillermondii (n=1)] and two DLTs (reported above). The treatment schema was modified to lower the dose of decitabine (10mg/m2/dose) and to reduce the duration from days 1-7/15-21 to 1-5/15-19. The duration of vorinostat was also reduced from days 3-10/17-24 to 2-7/16-21 (Figure 1). In addition, anti-fungal prophylaxis with either an echinocandin or amphotericin agent was required. Despite these dose modifications, infectious complications remained common with 17/23 (74%) patients reporting Gr ≥3 infections including invasive fungal disease in 35% (8/23). In analyzing all 23 patients, the complete response rate (CR + CR with incomplete blood count recovery) was 39% (9/23). Fourteen patients (61%) were able to complete full protocol therapy and evaluable for response. The remaining 9 patients did not complete therapy, primarily due to treatment-related toxicities, and were not evaluable. Nine of the 14 patients (64%) achieved a complete response with the remaining 5 reporting stable disease (36%). Minimal residual disease (MRD) testing via flow cytometry was performed on 7 of 9 patients who achieved a CR with a median level of 0.087% MRD (range, 0.00% to 1.6%) detected. Overall survival at 6 months was 35.1% (95% CI, 16.0 - 54.9) and 23.4% (95% CI, 7.8 - 43.6) at 1-year. Death was reported in 18/23 (78%) patients at a median of 10 weeks from study start (range, 3-138). Cause of death was attributed to refractory leukemia (n=8), treatment related toxicity (n=5), infection (n=3) and transplant-related toxicity (n=2). Despite encouraging response rates including low MRD, the combination of decitabine and vorinostat with intensive chemotherapy in this patient population was determined not to be feasible. A future follow-up study with a less intensive chemotherapy backbone is needed to determine if these two promising epigenetic agents can be successfully incorporated into the treatment of pediatric ALL. This study is registered at http://www.clinicaltrials.gov as NCT01483690. Disclosures Wayne: Kite Pharma: Honoraria, Other: Travel support, Research Funding; Spectrum Pharmaceuticals: Honoraria, Other: Travel Support, Research Funding; Pfizer: Consultancy, Honoraria, Other: Travel Support; Medimmune: Honoraria, Other: Travel Support, Research Funding; NIH: Patents & Royalties.

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