Evolutionary Emergence of Drug Resistance in Candida Opportunistic Pathogens

Fungal infections, such as candidiasis caused by Candida, pose a problem of growing medical concern. In developed countries, the incidence of Candida infections is increasing due to the higher survival of susceptible populations, such as immunocompromised patients or the elderly. Existing treatment options are limited to few antifungal drug families with efficacies that vary depending on the infecting species. In this context, the emergence and spread of resistant Candida isolates are being increasingly reported. Understanding how resistance can evolve within naturally susceptible species is key to developing novel, more effective treatment strategies. However, in contrast to the situation of antibiotic resistance in bacteria, few studies have focused on the evolutionary mechanisms leading to drug resistance in fungal species. In this review, we will survey and discuss current knowledge on the genetic bases of resistance to antifungal drugs in Candida opportunistic pathogens. We will do so from an evolutionary genomics perspective, focusing on the possible evolutionary paths that may lead to the emergence and selection of the resistant phenotype. Finally, we will discuss the potential of future studies enabled by current developments in sequencing technologies, in vitro evolution approaches, and the analysis of serial clinical isolates.

Download Full-text

CandidaInfections, Causes, Targets, and Resistance Mechanisms: Traditional and Alternative Antifungal Agents

BioMed Research International ◽

10.1155/2013/204237 ◽

2013 ◽

Vol 2013 ◽

pp. 1-13 ◽

Cited By ~ 91

Author(s):

Claudia Spampinato ◽

Darío Leonardi

Keyword(s):

Antifungal Agents ◽

Fungal Infections ◽

Current Knowledge ◽

Resistance Mechanisms ◽

Antifungal Drugs ◽

Diagnostic Methods ◽

Opportunistic Pathogens ◽

Yeast Infection ◽

Life Threatening ◽

Therapeutic Alternatives

The genusCandidaincludes about 200 different species, but only a few species are human opportunistic pathogens and cause infections when the host becomes debilitated or immunocompromised.Candidainfections can be superficial or invasive. Superficial infections often affect the skin or mucous membranes and can be treated successfully with topical antifungal drugs. However, invasive fungal infections are often life-threatening, probably due to inefficient diagnostic methods and inappropriate initial antifungal therapies. Here, we briefly review our current knowledge of pathogenic species of the genusCandidaand yeast infection causes and then focus on current antifungal drugs and resistance mechanisms. An overview of new therapeutic alternatives for the treatment ofCandidainfections is also provided.

Download Full-text

Autophagy and salivary gland cancer: A putative target for salivary gland tumors

Tumor Biology ◽

10.1177/1010428320980568 ◽

2020 ◽

Vol 42 (12) ◽

pp. 101042832098056

Author(s):

Evangelos Koustas ◽

Panagiotis Sarantis ◽

Margarita Theodorakidou ◽

Michalis V Karamouzis ◽

Stamatios Theocharis

Keyword(s):

Salivary Gland ◽

Current Knowledge ◽

Treatment Options ◽

Treatment Strategies ◽

In Vivo Studies ◽

Salivary Gland Cancer ◽

Number Of Patients ◽

Salivary Gland Carcinomas

Salivary gland carcinomas are a group of heterogeneous tumors of different histological subtypes, presenting relatively low incidence but the entire variable of types. Although novel treatment options for salivary gland carcinomas patients’ outcomes have improved, the treatment of this type of cancer is still not standardized. In addition, a significant number of patients, with a lack of optimal treatment strategies, have reduced survival. In the last two decades, a plethora of evidence pointed to the importance of autophagy, an essential catabolic process of cytoplasmatic component digestion, in cancer. In vitro and in vivo studies highlight the importance of autophagy in salivary gland carcinomas development as a tumor suppressor or promoter mechanism. Despite the potential of autophagy in salivary gland carcinomas development, no therapies are currently available that specifically focus on autophagy modulation in salivary gland carcinomas. In this review, we summarize current knowledge and clinical trials in regard to the interplay between autophagy and the development of salivary gland carcinomas. Autophagy manipulation may be a putative therapeutic strategy for salivary gland carcinomas patients.

Download Full-text

Antimycotic drugs and their mechanisms of resistance to Candida species

Current Drug Targets ◽

10.2174/1389450122666210719124143 ◽

2021 ◽

Vol 22 ◽

Author(s):

Sweety Dahiya ◽

Namita Sharma ◽

Aruna Punia ◽

Pooja Choudhary ◽

Prity Gulia ◽

...

Keyword(s):

Drug Resistance ◽

Candida Species ◽

Molecular Mechanisms ◽

Fungal Infections ◽

Treatment Strategies ◽

Distinct Species ◽

Antifungal Drugs ◽

Antifungal Drug ◽

Success Rates ◽

Antifungal Drug Resistance

: Fungal infections have shown an upsurge in recent decades, mainly because of the increasing number of immunocompromised patients, and the occurrence of invasive candidiasis is found to be 7-15 folds greater than that of invasive aspergillosis. The genus Candida comprises of more than 150 distinct species; however, only a few of them are found to be pathogenic to humans. Mortality rates of Candida species are found to be around 45%, and the reasons for this intensified mortality are inefficient diagnostic techniques and unfitting initial treatment strategies. There are only a few antifungal drug classes that are employed for the remedy of invasive fungal infections, including azoles, polyenes, echinocandins, and pyrimidine analogs. During the last 2-3 decades, the usage of antifungal drugs has increased several folds, due to which the reports of escalating antifungal drug resistance have also been recorded. The resistance is mostly to the triazole-based compounds. Due to antifungal drug resistance, the success rates of treatment have been reduced and major changes have been observed in the frequency of fungal infections. In this review, we have summarized the major molecular mechanisms for the development of antifungal drug resistance.

Download Full-text

Fungal biofilm architecture produces hypoxic microenvironments that drive antifungal resistance

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2003700117 ◽

2020 ◽

Vol 117 (36) ◽

pp. 22473-22483 ◽

Cited By ~ 2

Author(s):

Caitlin H. Kowalski ◽

Kaesi A. Morelli ◽

Daniel Schultz ◽

Carey D. Nadell ◽

Robert A. Cramer

Keyword(s):

Drug Resistance ◽

Fungal Infections ◽

Antifungal Drugs ◽

Antifungal Drug ◽

Drug Resistant ◽

Antifungal Drug Resistance ◽

Oxygen Gradients ◽

Biofilm Architecture

Human fungal infections may fail to respond to contemporary antifungal therapies in vivo despite in vitro fungal isolate drug susceptibility. Such a discrepancy between in vitro antimicrobial susceptibility and in vivo treatment outcomes is partially explained by microbes adopting a drug-resistant biofilm mode of growth during infection. The filamentous fungal pathogenAspergillus fumigatusforms biofilms in vivo, and during biofilm growth it has reduced susceptibility to all three classes of contemporary antifungal drugs. Specific features of filamentous fungal biofilms that drive antifungal drug resistance remain largely unknown. In this study, we applied a fluorescence microscopy approach coupled with transcriptional bioreporters to define spatial and temporal oxygen gradients and single-cell metabolic activity withinA. fumigatusbiofilms. Oxygen gradients inevitably arise duringA. fumigatusbiofilm maturation and are both critical for, and the result of,A. fumigatuslate-stage biofilm architecture. We observe that these self-induced hypoxic microenvironments not only contribute to filamentous fungal biofilm maturation but also drive resistance to antifungal treatment. Decreasing oxygen levels toward the base ofA. fumigatusbiofilms increases antifungal drug resistance. Our results define a previously unknown mechanistic link between filamentous fungal biofilm physiology and contemporary antifungal drug resistance. Moreover, we demonstrate that drug resistance mediated by dynamic oxygen gradients, found in many bacterial biofilms, also extends to the fungal kingdom. The conservation of hypoxic drug-resistant niches in bacterial and fungal biofilms is thus a promising target for improving antimicrobial therapy efficacy.

Download Full-text

Carrier-Mediated Drug Uptake in Fungal Pathogens

Genes ◽

10.3390/genes11111324 ◽

2020 ◽

Vol 11 (11) ◽

pp. 1324

Author(s):

Mónica Galocha ◽

Inês Vieira Costa ◽

Miguel Cacho Teixeira

Keyword(s):

Drug Resistance ◽

Fungal Pathogens ◽

Fungal Infections ◽

Current Knowledge ◽

Pathogenic Fungi ◽

Resistance Mechanisms ◽

Antifungal Drugs ◽

Major Facilitator Superfamily ◽

Drug Uptake ◽

Human Pathogens

Candida, Aspergillus, and Cryptococcus species are the most frequent cause of severe human fungal infections. Clinically relevant antifungal drugs are scarce, and their effectiveness are hampered by the ability of fungal cells to develop drug resistance mechanisms. Drug effectiveness and drug resistance in human pathogens is very often affected by their “transportome”. Many studies have covered a panoply of drug resistance mechanisms that depend on drug efflux pumps belonging to the ATP-Binding Cassette and Major Facilitator Superfamily. However, the study of drug uptake mechanisms has been, to some extent, overlooked in pathogenic fungi. This review focuses on discussing current knowledge on drug uptake systems in fungal pathogens, highlighting the need for further studies on this topic of great importance. The following subjects are covered: (i) drugs imported by known transporter(s) in pathogenic fungi; and (ii) drugs imported by known transporter(s) in the model yeast Saccharomyces cerevisiae or in human parasites, aimed at the identification of their homologs in pathogenic fungi. Besides its contribution to increase the understanding of drug-pathogen interactions, the practical implications of identifying drug importers in human pathogens are discussed, particularly focusing on drug development strategies.

Download Full-text

Nanoemulsion as an Effective Treatment against Human-Pathogenic Fungi

mSphere ◽

10.1128/msphere.00729-19 ◽

2019 ◽

Vol 4 (6) ◽

Cited By ~ 1

Author(s):

Alexis Garcia ◽

Yong Yi Fan ◽

Sandeep Vellanki ◽

Eun Young Huh ◽

DiFernando Vanegas ◽

...

Keyword(s):

Drug Resistance ◽

Fungal Infections ◽

Pathogenic Fungi ◽

Antifungal Drugs ◽

Solid Organ ◽

Therapeutic Approaches ◽

Content Type ◽

New Therapeutic Approaches ◽

Development Of Resistance

ABSTRACT Infections triggered by pathogenic fungi cause a serious threat to the public health care system. In particular, an increase of antifungal drug-resistant fungi has resulted in difficulty in treatment. A limited variety of antifungal drugs available to treat patients has left us in a situation where we need to develop new therapeutic approaches that are less prone to development of resistance by pathogenic fungi. In this study, we demonstrate the efficacy of the nanoemulsion NB-201, which utilizes the surfactant benzalkonium chloride, against human-pathogenic fungi. We found that NB-201 exhibited in vitro activity against Candida albicans, including both planktonic growth and biofilms. Furthermore, treatments with NB-201 significantly reduced the fungal burden at the infection site and presented an enhanced healing process after subcutaneous infections by multidrug-resistant C. albicans in a murine host system. NB-201 also exhibited in vitro growth inhibition activity against other fungal pathogens, including Cryptococcus spp., Aspergillus fumigatus, and Mucorales. Due to the nature of the activity of this nanoemulsion, there is a minimized chance of drug resistance developing, presenting a novel treatment to control fungal wound or skin infections. IMPORTANCE Advances in medicine have resulted in the discovery and implementation of treatments for human disease. While these recent advances have been beneficial, procedures such as solid-organ transplants and cancer treatments have left many patients in an immunocompromised state. Furthermore, the emergence of immunocompromising diseases such as HIV/AIDS or other immunosuppressive medical conditions have opened an opportunity for fungal infections to afflict patients globally. The development of drug resistance in human-pathogenic fungi and the limited array of antifungal drugs has left us in a scenario where we need to develop new therapeutic approaches to treat fungal infections that are less prone to the development of resistance by pathogenic fungi. The significance of our work lies in utilizing a novel nanoemulsion formulation to treat topical fungal infections while minimizing risks of drug resistance development.

Download Full-text

Are Carbonic Anhydrases Suitable Targets to Fight Protozoan Parasitic Diseases?

Current Medicinal Chemistry ◽

10.2174/0929867325666180326160121 ◽

2019 ◽

Vol 25 (39) ◽

pp. 5266-5278 ◽

Cited By ~ 9

Author(s):

Katia D'Ambrosio ◽

Claudiu T. Supuran ◽

Giuseppina De Simone

Keyword(s):

Drug Resistance ◽

Animal Models ◽

Carbonic Anhydrase ◽

Drug Target ◽

Treatment Options ◽

Parasitic Diseases ◽

Carbonic Anhydrases ◽

Extensive Drug Resistance ◽

Protozoan Infections

Protozoans belonging to Plasmodium, Leishmania and Trypanosoma genera provoke widespread parasitic diseases with few treatment options and many of the clinically used drugs experiencing an extensive drug resistance phenomenon. In the last several years, the metalloenzyme Carbonic Anhydrase (CA, EC 4.2.1.1) was cloned and characterized in the genome of these protozoa, with the aim to search for a new drug target for fighting malaria, leishmaniasis and Chagas disease. P. falciparum encodes for a CA (PfCA) belonging to a novel genetic family, the η-CA class, L. donovani chagasi for a β-CA (LdcCA), whereas T. cruzi genome contains an α-CA (TcCA). These three enzymes were characterized in detail and a number of in vitro potent and selective inhibitors belonging to the sulfonamide, thiol, dithiocarbamate and hydroxamate classes were discovered. Some of these inhibitors were also effective in cell cultures and animal models of protozoan infections, making them of considerable interest for the development of new antiprotozoan drugs with a novel mechanism of action.

Download Full-text

Potential of Nanoparticles in Combating Candida Infections

Letters in Drug Design & Discovery ◽

10.2174/1570180815666181015145224 ◽

2019 ◽

Vol 16 (5) ◽

pp. 478-491 ◽

Cited By ~ 5

Author(s):

Faizan Abul Qais ◽

Mohd Sajjad Ahmad Khan ◽

Iqbal Ahmad ◽

Abdullah Safar Althubiani

Keyword(s):

Targeted Delivery ◽

Recent Progress ◽

Antifungal Agents ◽

Fungal Infections ◽

Fold Increase ◽

Antifungal Drugs ◽

Low Toxicity ◽

Candida Infections ◽

Made In

Aims: The aim of this review is to survey the recent progress made in developing the nanoparticles as antifungal agents especially the nano-based formulations being exploited for the management of Candida infections. Discussion: In the last few decades, there has been many-fold increase in fungal infections including candidiasis due to the increased number of immunocompromised patients worldwide. The efficacy of available antifungal drugs is limited due to its associated toxicity and drug resistance in clinical strains. The recent advancements in nanobiotechnology have opened a new hope for the development of novel formulations with enhanced therapeutic efficacy, improved drug delivery and low toxicity. Conclusion: Metal nanoparticles have shown to possess promising in vitro antifungal activities and could be effectively used for enhanced and targeted delivery of conventionally used drugs. The synergistic interaction between nanoparticles and various antifungal agents have also been reported with enhanced antifungal activity.

Download Full-text

Current Insights into Immunology and Novel Therapeutics of Atopic Dermatitis

Cells ◽

10.3390/cells10061392 ◽

2021 ◽

Vol 10 (6) ◽

pp. 1392

Author(s):

Hidaya A. Kader ◽

Muhammad Azeem ◽

Suhib A. Jwayed ◽

Aaesha Al-Shehhi ◽

Attia Tabassum ◽

...

Keyword(s):

Atopic Dermatitis ◽

Skin Diseases ◽

Current Knowledge ◽

Treatment Strategies ◽

Developed Countries ◽

Food Allergies ◽

Th2 Response ◽

Therapeutic Outcomes ◽

Environmental Agents ◽

Novel Treatment Strategies

Atopic dermatitis (AD) is one of the most prevalent inflammatory disease among non-fatal skin diseases, affecting up to one fifth of the population in developed countries. AD is characterized by recurrent pruritic and localized eczema with seasonal fluctuations. AD initializes the phenomenon of atopic march, during which infant AD patients are predisposed to progressive secondary allergies such as allergic rhinitis, asthma, and food allergies. The pathophysiology of AD is complex; onset of the disease is caused by several factors, including strong genetic predisposition, disrupted epidermal barrier, and immune dysregulation. AD was initially characterized by defects in the innate immune system and a vigorous skewed adaptive Th2 response to environmental agents; there are compelling evidences that the disorder involves multiple immune pathways. Symptomatic palliative treatment is the only strategy to manage the disease and restore skin integrity. Researchers are trying to more precisely define the contribution of different AD genotypes and elucidate the role of various immune axes. In this review, we have summarized the current knowledge about the roles of innate and adaptive immune responsive cells in AD. In addition, current and novel treatment strategies for the management of AD are comprehensively described, including some ongoing clinical trials and promising therapeutic agents. This information will provide an asset towards identifying personalized targets for better therapeutic outcomes.

Download Full-text

Reversal of Azole Resistance inCandida albicansby Sulfa Antibacterial Drugs

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00701-17 ◽

2017 ◽

Vol 62 (3) ◽

Cited By ~ 15

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.

Download Full-text