Antifungals: From Genomics to Resistance and the Development of Novel Agents | Book
Caister Academic Press
Alix T. Coste1
and Patrick Vandeputte2
1Institute of Microbiology, University Hospital Lausanne,1011 Lausanne, Switzerland; 2Groupe d'Etude des Interactions Hôte-Pathogène, L'UNAM Université d'Angers, and Laboratoire de Parasitologie-Mycologie, Centre Hospitalier Universitaire, Angers, France
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Infections caused by pathogenic fungi are a significant global problem: a situation exacerbated by the limited availability of good antifungal options. Being eukaryotic organisms, these pathogens are phylogenetically much closer to the human host than bacterial pathogens. This sets serious limits to the range of exploitable fungal-specific drug targets. The advent of 'omics' and other high throughput technologies in recent years has revolutionised the field of antifungal research permitting researchers to quickly identify novel compounds and gain greater insights into drug resistance mechanisms. Researchers can analyse the whole organism's response to any particular condition or compound thereby providing a deeper understanding of fungal biology and the host-fungus interaction.
In this book a panel of high-profile authors provides an overview of current antifungal research. Chapters are written from a molecular and genomic perspective and contain speculative models upon which to base future research efforts. Topics include: the molecular mechanisms responsible for antifungal resistance to the classical molecules, azoles, polyenes, and echinocandins; fungal biofilms; fungal-specific biological pathways that constitute potential new targets; strategy to potentiate existing antifungal agents; Impact of high throughput screenings of chemical compound collections; modulating the host response; antifungal vaccines; and animals models.
This volume is an essential reference for everyone with an interest in fungal pathogenesis. A recommended book for all biology and medical libraries.
"this multi-authored text on antifungals is both timely and well-conceived ... chapters combine modern fungal biology with insights from molecule biology to yield a valuable and instructive survey of this area ... this well-organized volume pulls together insights from molecular biology, fungal biology, and fungal genomics to give an excellent survey that would be especially useful to medicinal chemists, biologists, and those responsible for planning pre-clinical development programs. The authors are well chosen, represent leaders in their respective areas, and are clearly drawing from a very up-to-date understanding of fungal biology. In particular, the book's review of molecular approaches to target identification, target deconvolution, and mechanisms of resistance will be especially valuable to those working in this important area." from ChemMedChem (2015) 10: 1273-1274.
"This book provides a valuable background to the different approaches now becoming available. Twenty-nine authors drawn from 11 countries have combined to produce this timely and scholarly overview ... The topics covered are wide-ranging ... The book is well presented with informative, often coloured, explanatory diagrams, and an index which includes all mentions of particular compounds. The editors are to be congratulated on the selection of topics and contributors to produce such an instructive volume in such a fast-moving and topical field." from IMA Fungus (2015) 6: 28
"This book is a comprehensive and current assessment of antifungal drugs with a prominent emphasis on antifungal drug resistance and drug discovery ... the book focuses on recent advances in deciphering the molecular mechanisms of drug resistance ... This book will be extremely valuable to practitioners in medical mycology, including established and new researchers, clinicians and clinical microbiologists, and infectious disease specialists seeking a rapid update on the current state of antifungal drug resistance and antifungal development." from Clinical Infectious Diseases (2015) 61: 1213-1214.
"Reading this book was a real adventure, as the monograph brings new knowledge about an alarming problem of increasing fungal resistance and available antifungal therapy ... a valuable text for experts in the field of antifungal research. Each chapter is carefully written and easy to understand ... this well-written and presented work is highly useful for both fields of fungal research and should be read not only by scientists working in field of fungal resistance but also by experts in clinical field." from Gen. Physiol. Biophy. (2015) 34: 453-454.
"scientists working in the mycology field and industry scientists developing new antimicrobials will find this compilation very useful. Infectious disease physicians treating patients with fungal diseases will find this book enlightening ... This is an excellent addition to the personal or institutional library of those working in the field of mycology, antimicrobial drug development, or infectious diseases. It brings together in one publication, a compilation of papers from leading experts in fungal biology and the genetic and molecular basis of antifungal resistance." from Doodys
Molecular Mechanisms of Resistance of Candida spp. to Membrane-targeting Antifungals
Luís A. Vale Silva
Membrane-targeting antifungal drugs represent the most numerous group of available antifungals. Systemically available membrane-targeting drugs act either by inhibiting ergosterol biosynthesis or by binding ergosterol directly in the fungal cell membrane. Ergosterol biosynthesis inhibitors include the large group of azole drugs, as well as a few other drugs from three different chemical families: allylamines, morpholines and thiocarbamates. The sole representatives of ergosterol binding drugs are the polyenes, including two active compounds in clinical use: amphotericin B and nystatin. Various different mechanisms of resistance to membrane targeting drugs have been described. Resistance mechanisms may be grouped as alterations of the intracellular accumulation of the drug, of the drug target (target enzyme sequence alterations or upregulation), or of the sterol biosynthesis pathway. Often, different mechanisms combine in the same Candida spp. isolate, conferring stepwise increase in drug resistance. This chapter presents a review of the known mechanisms of resistance of Candida spp. to membrane-targeting antifungals currently in use to treat candidiasis.
Point Mutations and Membrane-targeting Antifungals Resistance in Aspergillus fumigatus and other non-Candida Species
Invasive fungal infections are occurring with an increasing frequency. The management of these infections is challenging and the mortality is high. These facts make clinicians to indiscriminately use antifungal agents to treat and prevent fungal infections. The increased use of these drugs has resulted in the development of resistance. Antifungal resistance is linked with different molecular mechanisms including alteration in drug target, reduction of the intracellular concentration of the drug, overexpression of the drug target, etc. The aim of this chapter is to summarize the mechanisms of intrinsic and acquired resistance to ergosterol biosynthesis inhibitors and polyenes in Aspergillus fumigatus and other non-Candida species due to point mutations in enzymes participating in ergosterol biosynthesis pathways. This chapter will focus mainly in azole drugs since azole resistance is one of the main problems that modern Mycology is facing. A comparison and correlation between yeasts and molds mechanism of resistance will be described and analyzed although it is challenged by the inherent differences existing between these groups of fungi.
Echinocandins: Resistance Mechanisms
Santosh Katiyar and Thomas Edlind
Echinocandins, including caspofungin, micafungin, and anidulafungin are semi-synthetic lipopeptides that inhibit β-1,3-glucan synthase and hence fungal cell wall synthesis. They display excellent to moderate activity versus most Candida and Aspergillus species, although acquired resistance increasingly compromises their use versus C. glabrata. A primary limitation is the intrinsic resistance of all other fungal pathogens. Genetic analysis of acquired resistance in Saccharomyces cerevisiae identified the integral membrane protein Fks1 as the echinocandin target. Mutations cluster into hot spots 1 and, less commonly, 2 and 3 which share a similar topology: within or adjacent to the outer leaflet of the plasma membrane, and flanking a central cytoplasmic domain containing the likely substrate binding and catalytic sites. The differential resistance demonstrated by certain Fks1 mutations is consistent with direct interaction between the mutated residues and echinocandin-specific side chains. Differential resistance is also conferred by sphingolipid biosynthesis pathway mutations, suggesting a tripartite model for echinocandin-Fks1-membrane interaction. Analysis of Fks1 hot spot regions from fungi that exhibit intrinsically reduced susceptibility (Candida parapsilosis) or resistance (including Fusarium and Scedosporium species) identified substitutions that are likely to contribute to those phenotypes. Additional contributors likely include a reduced role for β-1,3-glucan in intrinsically resistant fungi, and increased cell wall chitin or melanin. Support for these Fks1-independent mechanisms is provided by dimorphic fungi such as Histoplasma capsulatum that encode a single Fks1 but alternate between echinocandin susceptible and resistant in their hyphal and yeast phases, respectively.
Biofilms and Antifungal Resistance
Emily P. Fox, Sheena D. Singh-Babak, Nairi Hartooni and Clarissa J. Nobile
Infections caused by pathogenic fungi are a significant medical problem, as they are able to disseminate to nearly every organ of the human body and there are few classes of antifungal drugs available as therapeutic options. Fungal infections are even more difficult to manage when they are biofilm-associated due to the natural properties of the biofilm mode of growth. Like bacterial biofilms, fungal biofilms consist of adherent communities of cells that are attached to a substrate and to one another, and are enclosed in a protective extracellular matrix material. Biofilms in general are able to withstand much higher concentrations of antimicrobial agents compared to single free-floating (or planktonic) cells, making biofilm infections extremely challenging to treat. In this chapter, we review the current knowledge of biofilm formation in representative, pathogenic species from several phyla of fungi. We also discuss the molecular mechanisms of drug resistance in fungal biofilms, the current standards of care for treating these biofilm-associated infections, and strategies for overcoming challenges in developing new antifungal drugs with efficacies against biofilms.
Drug Combinations as a Strategy to Potentiate Existing Antifungal Agents
Dominique Sanglard and Leah Cowen
Antifungal treatments for combating fungal infections are usually administered as monotherapies. With the few antifungal agents available and the inevitable development of resistance in fungal pathogens, combination therapy may be a future alternative to augment the efficacy of existing agents by synergistic effects. This review gives an overview of attempts to identify effective in vitro or in vivo combination of known antifungals with each other and with other bioactive molecules. The search for synergistic drug combinations currently involves systematic screening of compounds libraries. The high number of possible combinations with their intensive experimental demand has stimulated in silico approaches predictive of drug synergisms. Here we summarize the achievements of these approaches that use mainly chemo-genomic methods in fungal model systems.
Approaches to Detect Alternative Mechanisms of Resistance to Systemic Antifungals
Resistance to antifungals is a major concern in the management of fungal infections, especially while the incidence of pathogens with a poor susceptibility to current treatments is rising. New therapeutic strategies could be developed through the discovery of completely new fungal-specific targets or through the identification of new effectors of resistance to existing antifungals. In addition to basic molecular resistance mechanisms that are well understood, there are also numerous additional effectors able to modulate fungi susceptibility to the four main classes of antifungals. These effectors are unable to drive resistance alone, but they are now believed to be crucial for the establishment and maintenance of drug resistance, as they constitute key modulators allowing the phenotypic expression of resistance acquired by basic mechanisms. Formerly limited, the approaches to detect such alternative resistance mechanisms to antifungals were profoundly renewed with the "omics" era, allowing the study of whole organism's response. This chapter will focus on the main strategies implemented in the last two decades, with a particular emphasis on high throughput technologies such as whole genome sequencing, transcriptomics, proteomics, and large-scale mutant collections screening.
New Antifungal Discovery from Existing Chemical Compound Collections
Olihile M. Sebolai and Adepemi O. Ogundeji
Immunosuppressive conditions, as a result of either HIV-infection or unintended consequences of using anti-rejection drugs in organ transplant patients, have led to an increase in host vulnerability to fungal diseases. These conditions create optimal environments for opportunistic infections to occur, and thus it is not coincidental that previously non-pathogenic fungal species have become new mycotic agents. The emergence of these new mycotic agents in clinical settings is also in parallel to a rise in drug resistance, which is an inherent trait in natural selection. Therefore, it is a challenge to keep up with these agents (some of which may initiate a mode of infection that is not targeted by current antifungal drugs) given the time for development and approval period required to have a new drug on the market. And to compound this, the usage of conventional drugs such as azoles and polyenes is often times characterised by clinical failure, particularly in persons who are immunocompromised. Thus a solution to the above could be the repurposing of existing chemical compounds (already FDA-approved) as “new” antimicrobial agents, whose previous mechanisms of action were thought to be negative. To date, reports have emerged documenting the antifungal activity of non-traditional antimicrobial drugs, or where they enhance the activity of other traditional antimicrobial drugs. This text will therefore explore literature concerning the application of non-traditional antimicrobial drugs such as the prototypical anti-inflammatory drug acetylsalicylic acid, and other compounds in controlling human fungal diseases.
Exploring New Insights into Fungal Biology as Novel Antifungal Drug Targets
Rebecca A. Hall and Robin C. May
Although there are currently a number of good antifungal therapies available for the treatment of invasive fungal disease, the growing use of immune suppressive therapies and the ageing population has led to widespread use of antifungals. This overuse has lead to the development of antifungal resistance. Therefore, there is an urgent need for the identification of novel drug targets. This chapter highlights some of the recent discoveries in fungal biology including CO2 sensing, quorum sensing, cell wall biogenesis and intracellular proliferation, and we discuss the potential of these discoveries in the search for novel antifungal drug targets.
Strategies for the Identification of the Mode-of-action of Antifungal Drug Candidates
The characterization of the mode-of-action of antifungal drug candidates - also termed target deconvolution - is an integral part in the pharmaceutical drug discovery pipeline. The classical methods that were used during decades for deciphering antifungal drug mode-of-action relied specifically on classical microscopy, basic biochemical and biophysical approaches and classical forward genetics. With the era of functional genomics and high-throughput experimentation technologies, the implementation of large-scale target deconvolution strategies has drastically reshaped the field of drug discovery. In particular, the individual or combined use of chemogenomics, high-throughput drug-target interaction assays, transcriptomics and high-throughput imaging, together with powerful computer-based approaches for the integrative and predictive analyses from multiple data, offer a completely new vision on the potential and perspectives of exploring drug-target interactions in drug discovery and chemical biology. In this chapter, an overview of the classical approaches in antifungal drug mode-of-action studies is presented as a historical perspective, followed by description of the modern, currently used or likely to be more developed, approaches for conducting large-scale antifungal drug candidate target deconvolution studies.
Genome Integrity: Mechanisms and Contribution to Antifungal Resistance
Raphaël Loll, Adeline Feri, Christophe d'Enfert and Mélanie Legrand
Along with a growing population of immunocompromised patients, a steady increase in the number of invasive fungal infections has been observed over the last decades. Among human fungal pathogens, Candida albicans is one of the most prevalent and can cause life-threatening infections in humans. Although antifungal treatments are available and routinely used against fungal infections, one of the major issues in the treatment of these infections is the appearance of antifungal resistant cells. Over the last decade, genome plasticity of fungal pathogens in general and C. albicans in particular has emerged to be an important factor that contributes to their ability to acquire resistance to antifungal drugs. In this chapter, we provide an overview of the most important genome rearrangements that have been shown to occur upon antifungal exposure and/or lead to antifungal resistance. We also review recent advances in another important aspect in the field of genome stability and antifungal resistance, which is the characterization of the molecular mechanisms that can drive or prevent genome rearrangements in fungal pathogens. Finally, we address the effect of such large-scale genome changes on the fitness of antifungal resistant cells.
Modulation of the Host Response to Control Invasive Fungal Infections
Flavie Courjol, Thierry Jouault and Chantal Fradin
Disruption of the host immune defense is one of the most important risk factors for invasive fungal infections (IFIs). Knowledge of both the immune factors involved in defense against fungi and the immune risk factors for IFIs is important to target specific immune functions in order to regulate them in patients at risk. Candida albicans, Aspergillus fumigatus and Cryptococcus neoformans are the most common fungal pathogens of humans. They are opportunistic pathogens, which can disseminate in hosts with acquired defects in immune homeostasis. Risk factors for IFIs caused by these three fungi are well-known. Different studies have reported immune defense against their invasion, highlighting putative immune targets for immunotherapy. Some pre-clinical and clinical trials using non-specific immunotherapies (leucocytes transfusion, growth factors and cytokines) have been tested. Although an antifungal immunotherapy has not been discovered yet, some of the assays have given promising results.
Antifungal Vaccines and Immunotherapeutics
Agostinho Carvalho, Cristina Cunha, Claudia Galosi and Luigina Romani
Fungal diseases represent an important immunological paradigm as they can result from either immune deficiency or hyper-inflammatory responses. The expanding number of patients suffering from life-threatening fungal diseases as a consequence of advances in medical care, alongside the frequently limited success of antifungal therapy, has resulted in unacceptable rates of mortality, morbidity and associated costs. Consequently, there is a pressing need for new treatments and preventive measures to combat fungal diseases and, towards this goal, safe and efficacious vaccines would constitute a major step forward. Thus, an improved understanding of the dynamics of the host-fungus interaction, together with the dissection of the mechanisms underlying heterogeneous immune responses to vaccines, set up the foundations to devise new successful vaccination strategies. This chapter reviews recent advances in innate and adaptive immunity to fungi, and highlights how antifungal mechanisms of resistance and tolerance might be exploited for the design of antifungal vaccines.
Animal Models to Study Fungal Virulence and Antifungal Drugs
Alix T. Coste and Sara Amorim-Vaz
Animal models are crucial tools and a prerequisite for any clinical trials, since both the anatomopathology of an infection and a drug's efficacy/toxicity can only be accurately assessed in vivo before being used in humans. Ideally good animal models are able to closely mimic human diseases and allow analysis of the pathology, pathogen virulence traits, host response patterns, and efficacy of potential treatments. In the world of drug design, animal models are used to determine effective dose, pharmacokinetics, pharmacodynamics, and toxicity. Unfortunately, the majority of pathogenic fungi have essentially humans as natural hosts, meaning that the perfect animal model does not exist. Optimized models have to be developed depending on the scientific question being addressed, and several animal models often have to be used in order to answer all the questions raised by a biological problem. In addition, several ethical and financial considerations could also affect the choice of the model. In this review we will focus on animal models. They are usefull to assess antifungal drug efficacy and/or resistance and to analyse host-pathogen interaction that aims to determine new drug targets. In this review, we will discuss mammalian models of infection, with mice as being the gold standard as well as alternative non-mammalian models, also called mini-host models. These models range from insects, with Galleria mellonella as gold standard, to single cell hosts such as eggs or amoeba, through vertebrate models such as zebrafish.
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(EAN: 9781910190012 9781910190029 Subjects: [microbiology] [medical microbiology] [molecular microbiology] [genomics] [mycology] )