scholarly journals Alexidine Dihydrochloride Has Broad-Spectrum Activities against Diverse Fungal Pathogens

mSphere ◽  
2018 ◽  
Vol 3 (5) ◽  
Author(s):  
Zeinab Mamouei ◽  
Abdullah Alqarihi ◽  
Shakti Singh ◽  
Shuying Xu ◽  
Michael K. Mansour ◽  
...  
Keyword(s):  
Mammalian Cell ◽  
Fungal Pathogens ◽  
Fungal Infections ◽  
Antifungal Drugs ◽  
Immunocompromised Patients ◽  
Cell Toxicity ◽  
Diverse Range ◽  
Content Type ◽  
Mammalian Cell Toxicity

ABSTRACT Invasive fungal infections due to Candida albicans, Aspergillus fumigatus, and Cryptococcus neoformans constitute a substantial threat to hospitalized immunocompromised patients. Further, the presence of drug-recalcitrant biofilms on medical devices and emergence of drug-resistant fungi, such as Candida auris, introduce treatment challenges with current antifungal drugs. Worse, currently there is no approved drug capable of obviating preformed biofilms, which increase the chance of infection relapses. Here, we screened a small-molecule New Prestwick Chemical Library, consisting of 1,200 FDA-approved off-patent drugs against C. albicans, C. auris, and A. fumigatus, to identify those that inhibit growth of all three pathogens. Inhibitors were further prioritized for their potency against other fungal pathogens and their ability to kill preformed biofilms. Our studies identified the bis-biguanide alexidine dihydrochloride (AXD) as a drug with the highest antifungal and antibiofilm activity against a diverse range of fungal pathogens. Finally, AXD significantly potentiated the efficacy of fluconazole against biofilms, displayed low mammalian cell toxicity, and eradicated biofilms growing in mouse central venous catheters in vivo, highlighting its potential as a pan-antifungal drug. IMPORTANCE The prevalence of fungal infections has seen a rise in the past decades due to advances in modern medicine leading to an expanding population of device-associated and immunocompromised patients. Furthermore, the spectrum of pathogenic fungi has changed, with the emergence of multidrug-resistant strains such as C. auris. High mortality related to fungal infections points to major limitations of current antifungal therapy and an unmet need for new antifungal drugs. We screened a library of repurposed FDA-approved inhibitors to identify compounds with activities against a diverse range of fungi in varied phases of growth. The assays identified alexidine dihydrochloride (AXD) to have pronounced antifungal activity, including against preformed biofilms, at concentrations lower than mammalian cell toxicity. AXD potentiated the activity of fluconazole and amphotericin B against Candida biofilms in vitro and prevented biofilm growth in vivo. Thus, AXD has the potential to be developed as a pan-antifungal, antibiofilm drug.

scholarly journals Alexidine dihydrochloride has broad spectrum a ctivities against diverse fungal pathogens

2018 ◽  
Author(s):  
Zeinab Mamouei ◽  
Abdullah Alqarihi ◽  
Shakti Singh ◽  
Shuying Xu ◽  
Michael K. Mansour ◽  
...  
Keyword(s):  
Mammalian Cell ◽  
Fungal Pathogens ◽  
Fungal Infections ◽  
Antifungal Drugs ◽  
Immunocompromised Patients ◽  
Drug Resistant ◽  
Cell Toxicity ◽  
Diverse Range ◽  
Mammalian Cell Toxicity

AbstractInvasive fungal infections due to Candida albicans, Aspergillus fumigatus and Cryptococcus neoformans, constitute a substantial threat to hospitalized, immunocompromised patients. Further, the presence of drug-recalcitrant biofilms on medical devices, and emergence of drug-resistant fungi such as Candida auris, introduce treatment challenges with current antifungal drugs. Worse, currently there is no approved drug capable of obviating preformed biofilms which increases the chance of infection relapses. Here, we screened a small molecule Prestwick Chemical Library, consisting of 1200 FDA approved off-patent drugs, against C. albicans, C. auris and A. fumigatus, to identify those that inhibit growth of all three pathogens. Inhibitors were further prioritized for their potency against other fungal pathogens, and their ability to kill preformed biofilms. Our studies identified the bis-biguanide Alexidine dihydrochloride (AXD), as a drug with the highest antifungal and anti-biofilm activity against a diverse range of fungal pathogens. Finally, AXD significantly potentiated the efficacy of fluconazole against biofilms, displayed low mammalian cell toxicity, and eradicated biofilms growing in mice central venous catheters in vivo, highlighting its potential as a pan-antifungal drug.ImportanceThe prevalence of fungal infections has seen a rise in the past decades due to advances in modern medicine leading to an expanding population of device-associated and immunocompromised patients. Furthermore, the spectrum of pathogenic fungi has changed, with the emergence of multi-drug resistant strains such as C. auris. High mortality related to fungal infections point to major limitations of current antifungal therapy, and an unmet need for new antifungal drugs. We screened a library of repurposed FDA approved inhibitors to identify compounds with activities against a diverse range of fungi, in varied phases of growth. The assays identified Alexidine dihydrochloride (AXD) to have pronounced antifungal activity including against preformed biofilms, at concentrations lower than mammalian cell toxicity. AXD potentiated the activity of fluconazole and amphotericin B against Candida biofilms in vitro, and prevented biofilm growth in vivo. Thus AXD has the potential to be developed as a pan-antifungal, anti-biofilm drug.

scholarly journals Novel Antifungal Drug Discovery Based on Targeting Pathways Regulating the Fungus-Conserved Upc2 Transcription Factor

2013 ◽  
Vol 58 (1) ◽  
pp. 258-266 ◽  
Author(s):  
Christina Gallo-Ebert ◽  
Melissa Donigan ◽  
Ilana L. Stroke ◽  
Robert N. Swanson ◽  
Melissa T. Manners ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Dna Binding ◽  
Fungal Pathogens ◽  
Direct Interaction ◽  
Antifungal Drugs ◽  
Sterol Biosynthesis ◽  
Content Type ◽  
Stressed Cells

ABSTRACTInfections byCandida albicansand related fungal pathogens pose a serious health problem for immunocompromised patients. Azole drugs, the most common agents used to combat infections, target the sterol biosynthetic pathway. Adaptation to azole therapy develops as drug-stressed cells compensate by upregulating several genes in the pathway, a process mediated in part by the Upc2 transcription factor. We have implemented a cell-based high-throughput screen to identify small-molecule inhibitors of Upc2-dependent induction of sterol gene expression in response to azole drug treatment. The assay is designed to identify not only Upc2 DNA binding inhibitors but also compounds impeding the activation of gene expression by Upc2. An AlphaScreen assay was developed to determine whether the compounds identified interact directly with Upc2 and inhibit DNA binding. Three compounds identified by the cell-based assay inhibited Upc2 protein level andUPC2-LacZgene expression in response to a block in sterol biosynthesis. The compounds were growth inhibitory and attenuated antifungal-induced sterol gene expressionin vivo. They did so by reducing the level of Upc2 protein and Upc2 DNA binding in the presence of drug. The mechanism by which the compounds restrict Upc2 DNA binding is not through a direct interaction, as demonstrated by a lack of DNA binding inhibitory activity using the AlphaScreen assay. Rather, they likely inhibit a novel pathway activating Upc2 in response to a block in sterol biosynthesis. We suggest that the compounds identified represent potential precursors for the synthesis of novel antifungal drugs.

scholarly journals Targeting Methionine Synthase in a Fungal Pathogen Causes a Metabolic Imbalance That Impacts Cell Energetics, Growth, and Virulence

mBio ◽  
2020 ◽  
Vol 11 (5) ◽  
Author(s):  
Jennifer Scott ◽  
Monica Sueiro-Olivares ◽  
Benjamin P. Thornton ◽  
Rebecca A. Owens ◽  
Howbeer Muhamadali ◽  
...  
Keyword(s):  
Beneficial Effect ◽  
Aspergillus Fumigatus ◽  
Fungal Pathogen ◽  
Fungal Pathogens ◽  
Antifungal Drugs ◽  
New Drugs ◽  
Methionine Synthase ◽  
Content Type ◽  
Metabolic Imbalance

ABSTRACT There is an urgent need to develop novel antifungals to tackle the threat fungal pathogens pose to human health. Here, we have performed a comprehensive characterization and validation of the promising target methionine synthase (MetH). We show that in Aspergillus fumigatus the absence of this enzymatic activity triggers a metabolic imbalance that causes a reduction in intracellular ATP, which prevents fungal growth even in the presence of methionine. Interestingly, growth can be recovered in the presence of certain metabolites, which shows that metH is a conditionally essential gene and consequently should be targeted in established infections for a more comprehensive validation. Accordingly, we have validated the use of the tetOFF genetic model in fungal research and improved its performance in vivo to achieve initial validation of targets in models of established infection. We show that repression of metH in growing hyphae halts growth in vitro, which translates into a beneficial effect when targeting established infections using this model in vivo. Finally, a structure-based virtual screening of methionine synthases reveals key differences between the human and fungal structures and unravels features in the fungal enzyme that can guide the design of novel specific inhibitors. Therefore, methionine synthase is a valuable target for the development of new antifungals. IMPORTANCE Fungal pathogens are responsible for millions of life-threatening infections on an annual basis worldwide. The current repertoire of antifungal drugs is very limited and, worryingly, resistance has emerged and already become a serious threat to our capacity to treat fungal diseases. The first step to develop new drugs is often to identify molecular targets in the pathogen whose inhibition during infection can prevent its growth. However, the current models are not suitable to validate targets in established infections. Here, we have characterized the promising antifungal target methionine synthase in great detail, using the prominent fungal pathogen Aspergillus fumigatus as a model. We have uncovered the underlying reason for its essentiality and confirmed its druggability. Furthermore, we have optimized the use of a genetic system to show a beneficial effect of targeting methionine synthase in established infections. Therefore, we believe that antifungal drugs to target methionine synthase should be pursued and additionally, we provide a model that permits gaining information about the validity of antifungal targets in established infections.

scholarly journals Understanding In-Silico Approaches to Design Synthetic Antifungal Peptides to Combat Fungal Infections like Mucormycosis

2021 ◽  
Vol 8 (6) ◽  
Author(s):  
Bajwa T ◽  
◽  
Sharma R ◽  
Keyword(s):  
In Silico ◽  
Fungal Pathogens ◽  
Fungal Infections ◽  
Structural Features ◽  
Antifungal Drugs ◽  
Diverse Range ◽  
Naturally Occurring ◽  
Antifungal Peptides ◽  
Range Of Functions

Antimicrobial peptides are the small sized molecule ranging in size from 2 to 9 kDa with expansive range of antimicrobial activity against bacteria, fungi, viruses etc. They are also used as first line of defense against various pathogens. With the emergence of various fungal infections in the present day and uprising antifungal resistance has made the choice of antifungal drugs very limited, the conventional drugs are slowly becoming ineffective to these fungal pathogens. Researchers have turned to these naturally occurring molecules which represent diverse range of functions and structural features but these naturally occurring peptides exhibit high toxicity, instability and low specificity towards the target which can be combatted by using various in silico and computational approaches to design and modify these AMPs in such a way that their efficiency is increased. In this article, we have specifically focused on Mucormycosis infection because of its high mortality rates and a very few synthetic AMPs have been produced against Mucorales considering the severity of this disease and the rapid surge in Mucormycosis cases emerged in the country. In this paper we will discuss about the present scenario of the disease, AMPs as antifungal therapy, role, classification of antifungal peptides, mechanism of action, advantages and limitations of natural AMPs, important physicochemical properties taken into account while designing synthetic AMPs (SAMPs) and the workflow pipeline to characterize and predict potential synthetic AMPs by using the existing web servers, databases and bioinformatics tools to develop new alternatives of conventional drugs available in the market against fungal infections.

scholarly journals The Use of Galleria mellonella Larvae to Identify Novel Antimicrobial Agents against Fungal Species of Medical Interest

2018 ◽  
Vol 4 (3) ◽  
pp. 113 ◽  
Author(s):  
Kevin Kavanagh ◽  
Gerard Sheehan
Keyword(s):  
Fungal Pathogens ◽  
Antimicrobial Agents ◽  
Galleria Mellonella ◽  
Fungal Infections ◽  
Fungal Species ◽  
Molecular Techniques ◽  
Antifungal Drugs ◽  
Immune Priming ◽  
Greater Wax Moth

The immune system of insects and the innate immune response of mammals share many similarities and, as a result, insects may be used to assess the virulence of fungal pathogens and give results similar to those from mammals. Larvae of the greater wax moth Galleria mellonella are widely used in this capacity and also for assessing the toxicity and in vivo efficacy of antifungal drugs. G. mellonella larvae are easy to use, inexpensive to purchase and house, and have none of the legal/ethical restrictions that are associated with use of mammals. Larvae may be inoculated by intra-hemocoel injection or by force-feeding. Larvae can be used to assess the in vivo toxicity of antifungal drugs using a variety of cellular, proteomic, and molecular techniques. Larvae have also been used to identify the optimum combinations of antifungal drugs for use in the treatment of recalcitrant fungal infections in mammals. The introduction of foreign material into the hemocoel of larvae can induce an immune priming effect which may operate independently with the activity of the antifungal drug. Procedures to identify this effect and limit its action are required.

scholarly journals Galleria mellonella for the Evaluation of Antifungal Efficacy against Medically Important Fungi, a Narrative Review

2020 ◽  
Vol 8 (3) ◽  
pp. 390 ◽  
Author(s):  
Sana Jemel ◽  
Jacques Guillot ◽  
Kalthoum Kallel ◽  
Françoise Botterel ◽  
Eric Dannaoui
Keyword(s):  
Fungal Pathogens ◽  
Galleria Mellonella ◽  
Fungal Infections ◽  
Antifungal Susceptibility ◽  
Antifungal Drugs ◽  
New Drugs ◽  
Development Of Resistance ◽  
Antifungal Efficacy

The treatment of invasive fungal infections remains challenging and the emergence of new fungal pathogens as well as the development of resistance to the main antifungal drugs highlight the need for novel therapeutic strategies. Although in vitro antifungal susceptibility testing has come of age, the proper evaluation of therapeutic efficacy of current or new antifungals is dependent on the use of animal models. Mammalian models, particularly using rodents, are the cornerstone for evaluation of antifungal efficacy, but are limited by increased costs and ethical considerations. To circumvent these limitations, alternative invertebrate models, such as Galleria mellonella, have been developed. Larvae of G. mellonella have been widely used for testing virulence of fungi and more recently have proven useful for evaluation of antifungal efficacy. This model is suitable for infection by different fungal pathogens including yeasts (Candida, Cryptococcus, Trichosporon) and filamentous fungi (Aspergillus, Mucorales). Antifungal efficacy may be easily estimated by fungal burden or mortality rate in infected and treated larvae. The aim of the present review is to summarize the actual data about the use of G. mellonella for testing the in vivo efficacy of licensed antifungal drugs, new drugs, and combination therapies.

scholarly journals Central Role of the Trehalose Biosynthesis Pathway in the Pathogenesis of Human Fungal Infections: Opportunities and Challenges for Therapeutic Development

2017 ◽  
Vol 81 (2) ◽  
Author(s):  
Arsa Thammahong ◽  
Srisombat Puttikamonkul ◽  
John R. Perfect ◽  
Richard G. Brennan ◽  
Robert A. Cramer
Keyword(s):  
Stress Responses ◽  
Biosynthetic Pathway ◽  
Fungal Infections ◽  
Pathogenic Fungi ◽  
Antifungal Drugs ◽  
Antifungal Drug ◽  
Medical Mycology ◽  
Content Type ◽  
Trehalose Biosynthesis

SUMMARY Invasive fungal infections cause significant morbidity and mortality in part due to a limited antifungal drug arsenal. One therapeutic challenge faced by clinicians is the significant host toxicity associated with antifungal drugs. Another challenge is the fungistatic mechanism of action of some drugs. Consequently, the identification of fungus-specific drug targets essential for fitness in vivo remains a significant goal of medical mycology research. The trehalose biosynthetic pathway is found in a wide variety of organisms, including human-pathogenic fungi, but not in humans. Genes encoding proteins involved in trehalose biosynthesis are mechanistically linked to the metabolism, cell wall homeostasis, stress responses, and virulence of Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus. While there are a number of pathways for trehalose production across the tree of life, the TPS/TPP (trehalose-6-phosphate synthase/trehalose-6-phosphate phosphatase) pathway is the canonical pathway found in human-pathogenic fungi. Importantly, data suggest that proteins involved in trehalose biosynthesis play other critical roles in fungal metabolism and in vivo fitness that remain to be fully elucidated. By further defining the biology and functions of trehalose and its biosynthetic pathway components in pathogenic fungi, an opportunity exists to leverage this pathway as a potent antifungal drug target. The goal of this review is to cover the known roles of this important molecule and its associated biosynthesis-encoding genes in the human-pathogenic fungi studied to date and to employ these data to critically assess the opportunities and challenges facing development of this pathway as a therapeutic target.

Design of Dermaseptin S3 Analogues having Bacterial Cell Selectivity without Mammalian Cell Toxicity

2001 ◽  
Vol 8 (4) ◽  
pp. 281-288 ◽  
Author(s):  
Song Shin ◽  
Sung Yang ◽  
Soo Eom ◽  
Woo Song ◽  
Yangmee Kim ◽  
...  
Keyword(s):  
Mammalian Cell ◽  
Bacterial Cell ◽  
Cell Toxicity ◽  
Cell Selectivity ◽  
Mammalian Cell Toxicity

scholarly journals In vivo Active Organometallic-containing Antimycotic Agents

2021 ◽  
Author(s):  
Riccardo Rubbiani ◽  
Tobias Weil ◽  
Noemi Tocci ◽  
Luciano Mastrobuoni ◽  
Severin Jeger ◽  
...  
Keyword(s):  
Fungal Infections ◽  
Care Home ◽  
Multidrug Resistant ◽  
Immunocompromised Patients ◽  
Fungal Strains ◽  
Global Problem

Fungal infections represent a global problem, notably for immunocompromised, patients in hospital, covid-19 patient wards and care home settings, and the ever-increasing emergence of multidrug resistant fungal strains is a...

scholarly journals Reversal of Azole Resistance inCandida albicansby Sulfa Antibacterial Drugs

2017 ◽  
Vol 62 (3) ◽  
Author(s):  
Hassan E. Eldesouky ◽  
Abdelrahman Mayhoub ◽  
Tony R. Hazbun ◽  
Mohamed N. Seleem
Keyword(s):  
Treatment Options ◽  
Antifungal Drugs ◽  
Infection Model ◽  
Azole Resistance ◽  
Global Public Health ◽  
Sulfa Drugs ◽  
Antibacterial Drugs ◽  
Content Type

ABSTRACTInvasive candidiasis presents an emerging global public health challenge due to the emergence of resistance to the frontline treatment options, such as fluconazole. Hence, the identification of other compounds capable of pairing with fluconazole and averting azole resistance would potentially prolong the clinical utility of this important group. In an effort to repurpose drugs in the field of antifungal drug discovery, we explored sulfa antibacterial drugs for the purpose of reversing azole resistance inCandida. In this study, we assembled and investigated a library of 21 sulfa antibacterial drugs for their ability to restore fluconazole sensitivity inCandida albicans. Surprisingly, the majority of assayed sulfa drugs (15 of 21) were found to exhibit synergistic relationships with fluconazole by checkerboard assay with fractional inhibitory concentration index (ΣFIC) values ranging from <0.0312 to 0.25. Remarkably, five sulfa drugs were able to reverse azole resistance in a clinically achievable range. The structure-activity relationships (SARs) of the amino benzene sulfonamide scaffold as antifungal agents were studied. We also identified the possible mechanism of the synergistic interaction of sulfa antibacterial drugs with azole antifungal drugs. Furthermore, the ability of sulfa antibacterial drugs to inhibitCandidabiofilm by 40%in vitrowas confirmed. In addition, the effects of sulfa-fluconazole combinations onCandidagrowth kinetics and efflux machinery were explored. Finally, using aCaenorhabditis elegansinfection model, we demonstrated that the sulfa-fluconazole combination does possess potent antifungal activityin vivo, reducingCandidain infected worms by ∼50% compared to the control.

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