scholarly journals Fungicide effects on human fungal pathogens: Cross-resistance to medical drugs and beyond

2021 ◽  
Vol 17 (12) ◽  
pp. e1010073
Author(s):  
Rafael W. Bastos ◽  
Luana Rossato ◽  
Gustavo H. Goldman ◽  
Daniel A. Santos
Keyword(s):  
Fungal Pathogens ◽  
Fungal Infections ◽  
Resistance Mechanism ◽  
Antifungal Resistance ◽  
Antifungal Drugs ◽  
Fungal Resistance ◽  
Cross Resistance ◽  
Term Therapy ◽  
Prior History ◽  
Plant Materials

Fungal infections are underestimated threats that affect over 1 billion people, and Candida spp., Cryptococcus spp., and Aspergillus spp. are the 3 most fatal fungi. The treatment of these infections is performed with a limited arsenal of antifungal drugs, and the class of the azoles is the most used. Although these drugs present low toxicity for the host, there is an emergence of therapeutic failure due to azole resistance. Drug resistance normally develops in patients undergoing azole long-term therapy, when the fungus in contact with the drug can adapt and survive. Conversely, several reports have been showing that resistant isolates are also recovered from patients with no prior history of azole therapy, suggesting that other routes might be driving antifungal resistance. Intriguingly, antifungal resistance also happens in the environment since resistant strains have been isolated from plant materials, soil, decomposing matter, and compost, where important human fungal pathogens live. As the resistant fungi can be isolated from the environment, in places where agrochemicals are extensively used in agriculture and wood industry, the hypothesis that fungicides could be driving and selecting resistance mechanism in nature, before the contact of the fungus with the host, has gained more attention. The effects of fungicide exposure on fungal resistance have been extensively studied in Aspergillus fumigatus and less investigated in other human fungal pathogens. Here, we discuss not only classic and recent studies showing that environmental azole exposure selects cross-resistance to medical azoles in A. fumigatus, but also how this phenomenon affects Candida and Cryptococcus, other 2 important human fungal pathogens found in the environment. We also examine data showing that fungicide exposure can select relevant changes in the morphophysiology and virulence of those pathogens, suggesting that its effect goes beyond the cross-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 Acylhydrazones as Antifungal Agents Targeting the Synthesis of Fungal Sphingolipids

2018 ◽  
Vol 62 (5) ◽  
Author(s):  
Cristina Lazzarini ◽  
Krupanandan Haranahalli ◽  
Robert Rieger ◽  
Hari Krishna Ananthula ◽  
Pankaj B. Desai ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Antifungal Agents ◽  
Fungal Infections ◽  
Antifungal Drugs ◽  
Fungal Resistance ◽  
Content Type ◽  
Highly Active ◽  
Pharmacokinetic Properties ◽  
Pass Through

ABSTRACTThe incidence of invasive fungal infections has risen dramatically in recent decades. Current antifungal drugs are either toxic, likely to interact with other drugs, have a narrow spectrum of activity, or induce fungal resistance. Hence, there is a great need for new antifungals, possibly with novel mechanisms of action. Previously our group reported an acylhydrazone called BHBM that targeted the sphingolipid pathway and showed strong antifungal activity against several fungi. In this study, we screened 19 derivatives of BHBM. Three out of 19 derivatives were highly active againstCryptococcus neoformansin vitroand had low toxicity in mammalian cells. In particular, one of them, called D13, had a high selectivity index and showed better activity in an animal model of cryptococcosis, candidiasis, and pulmonary aspergillosis. D13 also displayed suitable pharmacokinetic properties and was able to pass through the blood-brain barrier. These results suggest that acylhydrazones are promising molecules for the research and development of new antifungal agents.

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 Molecular Identification, Antifungal Susceptibility Testing, and Mechanisms of Azole Resistance in Aspergillus Species Received within a Surveillance Program on Antifungal Resistance in Spain

2019 ◽  
Vol 63 (9) ◽  
Author(s):  
Olga Rivero-Menendez ◽  
Juan Carlos Soto-Debran ◽  
Narda Medina ◽  
Jose Lucio ◽  
Emilia Mellado ◽  
...  
Keyword(s):  
Aspergillus Terreus ◽  
Fungal Infections ◽  
Novel Mutation ◽  
Antifungal Susceptibility ◽  
Resistance Mechanism ◽  
Sensu Stricto ◽  
Antifungal Resistance ◽  
Surveillance Program ◽  
Azole Resistance ◽  
Content Type

ABSTRACT Antifungal resistance is one of the major causes of the increasing mortality rates for fungal infections, especially for those caused by Aspergillus spp. A surveillance program was established in 2014 in the Spanish National Center for Microbiology for tracking resistance in the most prevalent Aspergillus species. A total of 273 samples were included in the study and were initially classified as susceptible or resistant according to EUCAST breakpoints. Several Aspergillus cryptic species were found within the molecularly identified isolates. Cyp51 mutations were characterized for Aspergillus fumigatus, Aspergillus terreus, and Aspergillus flavus sensu stricto strains that were classified as resistant. Three A. fumigatus sensu stricto strains carried the TR34/L98H resistance mechanism, while two harbored G54R substitution and one harbored the TR46/Y121F/T289A mechanism. Seventeen strains had no mutations in cyp51A, with ten of them resistant only to isavuconazole. Three A. terreus sensu stricto strains harbored D344N substitution in cyp51A, one of them combined with M217I, and another carried an A249G novel mutation. Itraconazole-resistant A. flavus sensu stricto strains harbored P220L and H349R alterations in cyp51A and cyp51C, respectively, that need further investigation on their implication in azole resistance.

scholarly journals Antifungal Resistance, Metabolic Routes as Drug Targets, and New Antifungal Agents: An Overview about Endemic Dimorphic Fungi

2017 ◽  
Vol 2017 ◽  
pp. 1-16 ◽  
Author(s):  
Juliana Alves Parente-Rocha ◽  
Alexandre Melo Bailão ◽  
André Correa Amaral ◽  
Carlos Pelleschi Taborda ◽  
Juliano Domiraci Paccez ◽  
...  
Keyword(s):  
Drug Targets ◽  
Antifungal Agents ◽  
Fungal Infections ◽  
Public Health Problem ◽  
Antifungal Drugs ◽  
Fungal Resistance ◽  
Immunocompromised Patients ◽  
Dimorphic Fungi ◽  
Novel Drug ◽  
Novel Drug Targets

Diseases caused by fungi can occur in healthy people, but immunocompromised patients are the major risk group for invasive fungal infections. Cases of fungal resistance and the difficulty of treatment make fungal infections a public health problem. This review explores mechanisms used by fungi to promote fungal resistance, such as the mutation or overexpression of drug targets, efflux and degradation systems, and pleiotropic drug responses. Alternative novel drug targets have been investigated; these include metabolic routes used by fungi during infection, such as trehalose and amino acid metabolism and mitochondrial proteins. An overview of new antifungal agents, including nanostructured antifungals, as well as of repositioning approaches is discussed. Studies focusing on the development of vaccines against antifungal diseases have increased in recent years, as these strategies can be applied in combination with antifungal therapy to prevent posttreatment sequelae. Studies focused on the development of a pan-fungal vaccine and antifungal drugs can improve the treatment of immunocompromised patients and reduce treatment costs.

scholarly journals Synergistic Effects of Amiodarone and Fluconazole on Candida tropicalis Resistant to Fluconazole

2013 ◽  
Vol 57 (4) ◽  
pp. 1691-1700 ◽  
Author(s):  
Cecília Rocha da Silva ◽  
João Batista de Andrade Neto ◽  
José Júlio Costa Sidrim ◽  
Maria Rozzelê Ferreira Ângelo ◽  
Hemerson Iury Ferreira Magalhães ◽  
...  
Keyword(s):  
Candida Tropicalis ◽  
Inhibitory Concentration ◽  
Fungal Infections ◽  
Synergistic Effects ◽  
Antifungal Drugs ◽  
Cross Resistance ◽  
Combination Drug ◽  
Content Type ◽  
Effective Strategies ◽  
Drug Of Choice

ABSTRACTThere have recently been significant increases in the prevalence of systemic invasive fungal infections. However, the number of antifungal drugs on the market is limited in comparison to the number of available antibacterial drugs. This fact, coupled with the increased frequency of cross-resistance, makes it necessary to develop new therapeutic strategies. Combination drug therapies have become one of the most widely used and effective strategies to alleviate this problem. Amiodarone (AMD) is classically used for the treatment of atrial fibrillation and is the drug of choice for patients with arrhythmia. Recent studies have shown broad antifungal activity of the drug when administered in combination with fluconazole (FLC). In the present study, we induced resistance to fluconazole in six strains ofCandida tropicalisand evaluated potential synergism between fluconazole and amiodarone. The evaluation of drug interaction was determined by calculating the fractional inhibitory concentration and by performing flow cytometry. We conclude that amiodarone, when administered in combination with fluconazole, exhibits activity against strains ofC. tropicalisthat are resistant to fluconazole, which most likely occurs via changes in the integrity of the yeast cell membrane and the generation of oxidative stress, mitochondrial dysfunction, and DNA damage that could lead to cell death by apoptosis.

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 Anticapsular and Antifungal Activity of α-Cyperone

Antibiotics ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 51
Author(s):  
Connor Horn ◽  
Govindsamy Vediyappan
Keyword(s):  
Antifungal Activity ◽  
Fungal Pathogens ◽  
Fungal Infections ◽  
Antifungal Drugs ◽  
Cyperus Rotundus ◽  
Drug Resistant ◽  
Fungal Virulence ◽  
Medical Needs ◽  
Number Of Patients ◽  
Immunosuppressed Patients

Fungal infections affect 300 million people and cause 1.5 million deaths globally per year. With the number of immunosuppressed patients increasing steadily, there is an increasing number of patients infected with opportunistic fungal infections such as infections caused by the species of Candida and Cryptococcus. In fact, the drug-resistant Can. krusei and the emerging pan-antifungal resistant Can. auris pose a serious threat to human health as the existing limited antifungals are futile. To further complicate therapy, fungi produce capsules and spores that are resistant to most antifungal drugs/host defenses. Novel antifungal drugs are urgently needed to fill unmet medical needs. From screening a collection of medicinal plant sources for antifungal activity, we have identified an active fraction from the rhizome of Cyperus rotundus, the nut grass plant. The fraction contained α-Cyperone, an essential oil that showed fungicidal activity against different species of Candida. Interestingly, the minimal inhibitory concentration of α-Cyperone was reduced 8-fold when combined with a clinical antifungal drug, fluconazole, indicating its antifungal synergistic potential and could be useful for combination therapy. Furthermore, α-Cyperone affected the synthesis of the capsule in Cryp. neoformans, a causative agent of fungal meningitis in humans. Further work on mechanistic understanding of α-Cyperone against fungal virulence could help develop a novel antifungal agent for drug-resistant fungal pathogens.

scholarly journals Visible Lights Combined with Photosensitizing Compounds Are Effective against Candida albicans Biofilms

2021 ◽  
Vol 9 (3) ◽  
pp. 500 ◽  
Author(s):  
Priyanka Bapat ◽  
Gurbinder Singh ◽  
Clarissa J. Nobile
Keyword(s):  
Candida Albicans ◽  
Photodynamic Therapy ◽  
Biofilm Formation ◽  
Fungal Pathogens ◽  
Fungal Infections ◽  
Therapeutic Strategies ◽  
Antifungal Drugs ◽  
Clinical Settings ◽  
Drug Resistant ◽  
Candida Albicans Biofilms

Fungal infections are increasing in prevalence worldwide, especially in immunocompromised individuals. Given the emergence of drug-resistant fungi and the fact that there are only three major classes of antifungal drugs available to treat invasive fungal infections, there is a need to develop alternative therapeutic strategies effective against fungal infections. Candida albicans is a commensal of the human microbiota that is also one of the most common fungal pathogens isolated from clinical settings. C. albicans possesses several virulence traits that contribute to its pathogenicity, including the ability to form drug-resistant biofilms, which can make C. albicans infections particularly challenging to treat. Here, we explored red, green, and blue visible lights alone and in combination with common photosensitizing compounds for their efficacies at inhibiting and disrupting C. albicans biofilms. We found that blue light inhibited biofilm formation and disrupted mature biofilms on its own and that the addition of photosensitizing compounds improved its antibiofilm potential. Red and green lights, however, inhibited biofilm formation only in combination with photosensitizing compounds but had no effects on disrupting mature biofilms. Taken together, these results suggest that photodynamic therapy may be an effective non-drug treatment for fungal biofilm infections that is worthy of further exploration.

scholarly journals Antifungal Drug Repurposing

Antibiotics ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 812
Author(s):  
Jong H. Kim ◽  
Luisa W. Cheng ◽  
Kathleen L. Chan ◽  
Christina C. Tam ◽  
Noreen Mahoney ◽  
...  
Keyword(s):  
Fungal Pathogens ◽  
Gene Promoter ◽  
Drug Repurposing ◽  
Antifungal Drugs ◽  
Fungal Resistance ◽  
Alternative Methods ◽  
Effective Control ◽  
Environmental Selection ◽  
Antifungal Action ◽  
Azole Fungicides

Control of fungal pathogens is increasingly problematic due to the limited number of effective drugs available for antifungal therapy. Conventional antifungal drugs could also trigger human cytotoxicity associated with the kidneys and liver, including the generation of reactive oxygen species. Moreover, increased incidences of fungal resistance to the classes of azoles, such as fluconazole, itraconazole, voriconazole, or posaconazole, or echinocandins, including caspofungin, anidulafungin, or micafungin, have been documented. Of note, certain azole fungicides such as propiconazole or tebuconazole that are applied to agricultural fields have the same mechanism of antifungal action as clinical azole drugs. Such long-term application of azole fungicides to crop fields provides environmental selection pressure for the emergence of pan-azole-resistant fungal strains such as Aspergillus fumigatus having TR34/L98H mutations, specifically, a 34 bp insertion into the cytochrome P450 51A (CYP51A) gene promoter region and a leucine-to-histidine substitution at codon 98 of CYP51A. Altogether, the emerging resistance of pathogens to currently available antifungal drugs and insufficiency in the discovery of new therapeutics engender the urgent need for the development of new antifungals and/or alternative therapies for effective control of fungal pathogens. We discuss the current needs for the discovery of new clinical antifungal drugs and the recent drug repurposing endeavors as alternative methods for fungal pathogen control.

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