At What Cost Echinocandin Resistance?

Journal of Infectious Diseases, Aug 2011

Cornelius J. Clancy, M. Hong Nguyen

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At What Cost Echinocandin Resistance?

Cornelius J. Clancy 0 1 M. Hong Nguyen 1 0 Veterans Affairs Pittsburgh Healthcare System , Pennsylvania 1 Department of Medicine, University of Pittsburgh - The treatment and prevention of infectious diseases caused by antimicrobialresistant pathogens is one of the great challenges confronting modern medicine. Meeting this challenge will require better understanding of the various factors that determine the emergence and spread of resistance. Major determinants of the rate and trajectory of the evolution of resistance include the size of the microbial population exposed to a given agent, mutation rates, and the effect of resistance mechanisms on microbial fitness [1, 2]. Fitness, defined in the Darwinian sense as the ability to survive and reproduce [3], has been extensively studied in bacteria and viruses [24]. In many cases, resistance comes at a fitness cost to the organism, which is evident as reduced replication rate, virulence, or transmissibility [2]. Efflux pumps or the synthesis of enzymes that modify antibiotics, for example, may reduce fitness by requiring greater energy and metabolic expenditures [5]. Mutations of genes targeted by antibiotics, on the other hand, may have deleterious effects on the essential cellular processes regulated by the gene products [6]. In some instances, however, resistance confers no change in microbial fitness or may even increase fitness [2], depending on the specific mutation, strain background, and experimental conditions [3, 4]. Moreover, initial decreases in fitness due to resistance may be restored over time by compensatory evolution, which can stabilize the resistant populations and render them as fit as susceptible organisms [2, 6]. Therefore, although the concept of fitness cost is useful, the relationship between resistance and the fitness of microbes is more complex than the term suggests [3]. Antifungal resistance has emerged as a major clinical problem in concert with the increasing populations of immunosuppressed hosts and hospitalized patients at risk for fungal infections. Antifungal resistance mechanisms are best understood for fluconazole among Candida species, the most common fungal pathogens. Fluconazole and other azoles are particularly prone to the emergence of resistance, because they are often prescribed for extended periods on a repeated basis, and their fungistatic activity leaves a larger residual population of Candida than do fungicidal drugs [1]. In addition, there are multiple mechanisms by which Candida strains can become fluconazole resistant, including overexpression or mutation of ERG11 (the gene encoding the target enzyme lanosterol 14-a demethylase), expression of efflux pumps, gain-of-function mutations in a transcription factor regulating efflux pump expression, loss of mitochondrial function, and changes in chromosome number [1, 712]. Given these diverse mechanisms, the effect of fluconazole resistance on fitness is at least as complex as that for bacteria and antibiotic resistance. In fact, studies have reported both increased and reduced candidal fitness, disparities between fitness in vitro and in vivo, and the presence and absence of compensatory evolution [1, 712]. In this issue of the Journal, Ben-Ami et al report the first study of the effect of echinocandin resistance on fitness of a Candida species [13]. The echinocandins have become front-line agents for the treatment of candidiasis because of their broad-spectrum activity, including against fluconazole-resistant Candida strains [14]. These agents inhibit the synthesis of 1,3-b-D-glucan synthase, an enzyme complex that encodes a major constituent of the cell wall. To date, echinocandin resistance remains relatively rare among clinical isolates [15], although reports are increasing in number [16]. Compared with azole resistance, the emergence of echinocandin resistance is limited by the candidacidal activity of the class and the fact that the only known mechanism is mutation in the FKS genes encoding the glucan synthase complex [17]. As such, the study of fitness costs associated with echinocandin resistance may be more straightforward than with azole resistance. In their study, Ben-Ami and colleagues compared resistant Candida albicans strains in which homozygous fks1-S645F or fks1-S645P mutations arose in response to echinocandin exposure in clinical or laboratory settings with their respective wild-type FKS1 parents. To date, these are the most commonly reported FKS mutations. Grown in the absence of an echinocandin, the fks1 mutants exhibited reduced maximum catalytic velocity (Vmax) of glucan synthase, thickened cell walls due to increased chitin content, decreased growth rates and filamentation in vitro, and significantly attenuated virulence in Drosophila melanogaster flies and mice. Strikingly, the aberrant phenotypes correlated directly with chitin content. Increased chitin also was associated with a blunted Dectin-1 mediated inflammatory response from mur (...truncated)


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Cornelius J. Clancy, M. Hong Nguyen. At What Cost Echinocandin Resistance?, Journal of Infectious Diseases, 2011, pp. 499-501, 204/4, DOI: 10.1093/infdis/jir355