Antifungals: From Genomics to Resistance and the Development of Novel Agents

This book is a comprehensive and current assessment of antifungal drugs with a prominent emphasis on antifungal drug resistance and drug discovery. Invasive fungal infections result in approximately 1.4 million deaths annually, with most deaths due to infection with Cryptococcus, Candida, and Aspergillus species. Successful patient management requires antifungal therapy, yet treatment options are highly restricted, because existing systemic antifungal drugs comprise only limited chemical classes, including azoles, echinocandins, polyenes, and flucytosine. Patient outcomes are further compromised by the development of antifungal drug resistance. This book is organized by major themes and includes chapters on drug resistance and overcoming resistance, the discovery of novel microbe- and host-directed antifungal agents, and in vivo models of fungal infections. The effectiveness of each chapter reflects the prominent expertise of the authors. Chapters are well constructed and easy to read, with a comprehensive overview of critical issues related to each drug class or related topic, with attention to highly molecular facets of antifungal drug action and an eye toward either clinical experience or new applications. Collectively, the overall monograph works very well. The editors’ preface emphasizes that the book focuses on recent advances in deciphering the molecular mechanisms of drug resistance. The title, Antifungals, may suggest a broader view of antifungal drugs (eg, pharmacokinetic properties), but the subtitle, From Genomics to Resistance and the Development of Novel Agents, more aptly captures the essence of the book. The emphasis is apparent in the first 3 chapters, which provide overviews of classic membrane active antifungal drugs, azoles and polyenes, and the newer cell wall–active echinocandins, with detailed discussions of the molecular aspects of resistance in Candida and Aspergillus species. Antifungal resistance may result from selection for inherently resistant (primary resistant) species (eg, Candida krusei with azoles) or from acquired resistance during therapy. The molecular mechanisms for primary and acquired resistance are often the same and may reflect a different genetic wiring or prior selection from the environment, as in the case of Aspergillus resistant to highly active triazole agents. The chapter by Garcia-Effron is comprehensive and nicely incorporates into the dialogue computational models of the azole drug target, Cyp51a, illustrating changes in drug-target interactions following acquisition of resistance conferring mutations. The chapter by Katiyar and Edlind on echinocandin resistance provides a succinct overview of clinically related acquired resistance involving modification of glucan synthase subunits encoded by FKS genes. There is no discussion of adaptive compensatory mechanisms important for stabilizing cells in the presence of drug, but the authors do nicely describe the potential for other cellular mechanisms to modulate in vitro sensitivity. Biofilms are universal resistance mechanisms for fungi and bacteria, and Fox et al cover this subject effectively in their chapter. Overcoming and preventing resistance is a critical issue for all anti-infectives. To address this issue, Sanglard and Cowen revisit a combination strategy using existing drugs, as well as chemogenetics, to predict synergistic combinations of antifungal agents and other drugs, such as those mediated by stress modulator HSP90, to improve efficacy and help limit emergence of resistance. The past decade has seen major advances in dissection of molecular mechanisms of drug resistance. The power of this approach is very much on display in the chapter by Vandeputte, which describes the use of genomics, mutant analysis, and proteomics to identify novel resistance and/or drug tolerance mechanisms. There is an urgent need for new classes of antifungal agents, and Sebolai and Ogundeji explore the potential of Food and Drug Administration–approved drug libraries and natural products, including plant extracts affect microbial growth or host response. As a complement to this chapter, Hall and May describe well-defined biological processes, which may be used as potential antifungal targets, such as adenylyl cylase and carbonic anhydrase or other facets of cell wall glucan and/or mannan biosynthesis. Along with new antifungal drugs and chemical classes is the need to identify mode of action, which is nicely covered in the chapter by Znaidi, which describes classic and modern approaches to assessing mode of action. One of the important realizations of genetic studies on yeasts, such as Candida albicans and Candida glabrata, is how plastic these genomes behave, especially in response to drug stress. Genomic alternations in karyotype, especially aneuploidy, which result in gain or loss of partial segments of whole chromosomes, play an important role in up-regulating genetic mechanisms contributing to drug resistance and virulence. Loll-Krippleber et al very nicely describe the importance of genome integrity and the factors influencing it. Their chapter is somewhat out of place in the book and would have been better positioned at the end of the drug resistance mechanisms section, but this is a minor point. The development of agents that modulate host response to fungal pathogens is an important area that needs more attention. Courjol et al offer a helpful overview of the host response to fungal infections and risk factors for development of disease. Their chapter concisely describes the importance of macrophages, neutrophils, cytotoxic T-cell activation, and the inflammatory response in this process, as well as other critical adaptive and innate components of the immune response. It sets the stage for a chapter providing a provocative discussion of vaccine strategies and the potential value of exploiting CD8+ T-cell immunity for this purpose, as well as an overview of immunotherapy approaches. The concluding chapter by Coste and Amorim-Vaz provides a much-needed overview of the multitude of current animal models of infection used to study response to antifungal drugs and virulence factors including rodents, zebra fish, and moth larvae. 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. Potential conflict of interest. D. S. P. receives grant support from the National Institutes of Health, Astellas, Scynexis, and Cidara. The author has submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

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