At What Cost Echinocandin Resistance?
Cornelius J. Clancy
0
1
M. Hong Nguyen
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Veterans Affairs Pittsburgh Healthcare System
,
Pennsylvania
1
Department of Medicine, University of Pittsburgh
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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)