bioRxiv (Cold Spring Harbor Laboratory),
Journal Year:
2024,
Volume and Issue:
unknown
Published: Nov. 9, 2024
Abstract
Background
Fungal
infections
are
an
increasing
concern,
particularly
among
immunocompromised
patients
and
those
with
comorbidities
who
require
multiple
medications.
However,
the
effects
of
drugs
targeting
human
pathways
on
fungal
cells,
whether
they
influence
antifungal
drug
responses,
poorly
understood.
Methods
We
systematically
analyzed
clinical
guidelines
to
shortlist
non-antifungal
commonly
used
in
conditions
that
increase
likelihood
infections.
Focusing
most
prevalent
pathogen,
we
then
tested
how
these
affected
response
Candida
albicans
two
antifungals,
fluconazole
anidulafungin.
Drug
interactions
identified
were
further
assessed
using
checkerboard
disk
diffusion
assays.
Finally,
treatment
efficacy
combination
negatively
interacting
was
evaluated
vivo
Galleria
mellonella
model
disseminated
C.
infection.
Findings
Out
119
frequently
co-administered
antifungals
40
associated
a
high
risk
infections,
34
compounds
,
reducing
or
antagonising
efficacy,
several
through
resistance
tolerance.
Notably,
combinations
carvedilol
loperamide
promoted
both
cultures
.
Interpretation
Our
findings
suggest
medications
taken
by
at
regularly
act
pathogens
can
affect
effectiveness
antifungals.
propose
acting
may
be
underestimated
factor
contributing
evolution
tolerance
resistance.
Nature Communications,
Journal Year:
2025,
Volume and Issue:
16(1)
Published: Jan. 25, 2025
Multidrug
resistance
in
the
pathogenic
fungus
Candida
glabrata
is
a
growing
global
threat.
Here,
we
study
mechanisms
of
multidrug
this
pathogen.
Exposure
C.
cells
to
micafungin
(an
echinocandin)
leads
isolation
mutant
exhibiting
echinocandin
and
azole
antifungals.
The
drug-resistant
phenotype
due
non-synonymous
mutation
(R70H)
gene
IPI1,
which
involved
pre-rRNA
processing.
Azole
ipi1R70H
depends
on
Pdr1
transcription
factor,
regulates
expression
transporters.
Ipi1
protein
physically
interacts
with
ribosome-related
chaperones
Ssb
Ssz1,
both
bind
Pdr1.
Ipi1-Ssb/Ssz1
complex
inhibits
Pdr1-mediated
glabrata,
contrast
Saccharomyces
cerevisiae
where
Ssz1
acts
as
positive
regulator
Furthermore,
exposure
reduces
metabolic
activity
cell
proliferation
mutant,
may
contribute
tolerance.
authors
show
that
processing,
pathogen
by
affecting
interactions
between
two
factor
transporter
expression.
Journal of Fungi,
Journal Year:
2025,
Volume and Issue:
11(2), P. 143 - 143
Published: Feb. 13, 2025
Antifungal
resistance
poses
a
critical
global
health
threat,
particularly
in
immuno-compromised
patients.
Beyond
the
traditional
mechanisms
rooted
heritable
and
stable
mutations,
distinct
phenomenon
known
as
heteroresistance
has
been
identified,
wherein
minority
of
resistant
fungal
cells
coexist
within
predominantly
susceptible
population.
Heteroresistance
may
be
induced
by
pharmacological
factors
or
non-pharmacological
agents.
The
reversible
nature
it
presents
significant
clinical
challenges,
can
lead
to
undetected
during
standard
susceptibility
testing.
As
allows
pathogens
survive
antifungal
treatment,
this
adaptive
strategy
often
leads
treatment
failure
recurring
infection.
Though
extensively
studied
bacteria,
limited
research
explored
its
occurrence
fungi.
This
review
summarizes
current
findings
on
mechanisms,
highlighting
implications
pressing
need
for
deeper
mechanism
insights.
We
aim
bring
together
latest
advances
field
heteroresistance,
summarizing
detail
characteristics,
inducing
factors,
molecular
significance,
describing
similarities
differences
between
tolerance
persistence.
Further
is
needed
understand
develop
more
effective
therapies
combat
infections.
Journal of Fungi,
Journal Year:
2025,
Volume and Issue:
11(4), P. 284 - 284
Published: April 4, 2025
Candida
glabrata
is
an
opportunistic,
pathogenic
fungus
that
increasingly
isolated
from
hospitalized
patients.
The
incidence
of
drug
tolerance,
heteroresistance,
and
resistance
on
the
rise
due
to
overuse
antifungal
drugs.
aim
this
study
was
expose
a
sensitive
C.
strain
sequentially
increasing
concentrations
two
drugs,
fluconazole,
azole
targets
ergosterol
biosynthesis,
or
caspofungin,
echinocandin
cell
wall
glucan
synthesis.
Analysis
drug-exposed
isolates
showed
development
chromosomal
abnormalities,
decreased
adhesion,
attenuated
virulence,
increase
in
efflux
pump
activity.
Furthermore,
whole
genome
sequencing
all
exposed
different
fluconazole
caspofungin
performed
determine
mutations
key
genes
could
correlate
with
observed
phenotypes.
Mutations
were
found
implicated
such
as
AWP,
PWP,
EPA
family
genes.
Isolates
higher
displayed
more
than
those
at
lower
concentrations.
Clinical Microbiology Reviews,
Journal Year:
2025,
Volume and Issue:
unknown
Published: April 22, 2025
SUMMARY
Vulvovaginal
candidiasis
(VVC)
is
a
prevalent
global
health
burden,
particularly
among
reproductive-aged
women.
Recurrent
VVC
affects
significant
proportion
of
this
population,
presenting
therapeutic
challenges.
The
predominant
pathogen,
Candida
albicans
,
opportunistically
transitions
from
commensal
organism
to
pathogen
when
microenvironmental
conditions
become
dysregulated.
Recently,
non-
species
have
gained
attention
for
their
reduced
antifungal
susceptibility
and
recurrence
tendencies.
Diagnosis
constrained
by
the
limitations
conventional
microbiological
techniques,
while
emerging
molecular
assays
offer
enhanced
detection
yet
lack
established
thresholds
differentiate
between
pathogenic
states.
Increasing
resistance
issues
are
encountered
traditional
azole-based
antifungals,
necessitating
innovative
approaches
that
integrate
microbiota
modulation
precision
medicine.
Therefore,
review
aims
systematically
explore
diversity,
drug
mechanisms,
biofilm
effects
species.
Vaginal
(VMB)
alterations
associated
with
were
also
examined,
focusing
on
interaction
Lactobacillus
spp.
fungi,
emphasizing
role
microbial
dysbiosis
in
disease
progression.
Finally,
potential
summarized,
particular
focus
use
probiotics
modulate
VMB
composition
restore
healthy
ecosystem
as
promising
treatment
strategy.
This
addresses
adopts
microbiota-centric
approach,
proposing
comprehensive
framework
personalized
management
reduce
improve
patient
outcomes.
Frontiers in Cellular and Infection Microbiology,
Journal Year:
2024,
Volume and Issue:
14
Published: June 25, 2024
Antifungal
resistance
and
antifungal
tolerance
are
two
distinct
terms
that
describe
different
cellular
responses
to
drugs.
describes
the
ability
of
a
fungus
grow
above
minimal
inhibitory
concentration
(MIC)
drug.
drug
susceptible
strains
slowly
at
concentrations.
Recent
studies
indicate
have
evolutionary
trajectories.
Superficial
candidiasis
bothers
millions
people
yearly.
Miconazole
has
been
used
for
topical
treatment
yeast
infections
over
40
years.
Yet,
fungal
miconazole
remains
relatively
low.
Here
we
found
clinical
isolates
Candida
albicans
had
profile
miconazole,
was
modulated
by
physiological
factors
including
temperature
medium
composition.
Exposure
non-tolerant
with
genetic
backgrounds
mainly
induced
development
tolerance,
not
resistance,
due
whole
chromosomal
or
segmental
amplification
chromosome
R.
The
efflux
gene
CDR1
required
maintenance
in
wild
type
but
gain
aneuploidy-mediated
tolerance.
Heat
shock
protein
Hsp90
calcineurin
were
essential
as
well
Our
study
indicates
is
predominant
mechanism
rapid
adaptation
C.
,
relevance
deserves
further
investigations.
Frontiers in Microbiology,
Journal Year:
2024,
Volume and Issue:
15
Published: July 30, 2024
Background
The
emergence
of
tolerance
to
antifungal
agents
in
Candida
albicans
complicates
the
treatment
fungal
infections.
Understanding
mechanisms
underlying
this
is
crucial
for
developing
effective
therapeutic
strategies.
Objective
This
study
aims
elucidate
genetic
and
molecular
basis
ketoconazole
C.
,
focusing
on
roles
chromosomal
aneuploidy,
Hsp90,
calcineurin.
Methods
wild-type
strain
SC5314
was
exposed
increasing
concentrations
(0.015–32
μg/mL)
select
tolerant
adaptors.
Disk
diffusion
spot
assays
were
used
assess
tolerance.
Whole-genome
sequencing
identified
changes
Hsp90
calcineurin
maintaining
investigated
using
specific
inhibitors
knockout
strains.
Results
Adaptors
exhibited
up
16
μg/mL,
a
significant
increase
from
parent
strain’s
inhibition
at
0.015
μg/mL.
All
adaptors
showed
amplification
chromosome
R,
with
29
having
trisomy
one
tetrasomy.
aneuploidy
unstable,
reverting
euploidy
losing
drug-free
conditions.
Both
essential
Inhibition
these
proteins
resulted
loss
efflux
gene
CDR1
not
required
development
Chromosome
R
tetrasomy
induce
cross-tolerance
other
azole
agents,
including
clotrimazole
miconazole,
but
classes,
such
as
echinocandins
pyrimidines,
exemplified
by
caspofungin
5-flucytosine.
Conclusion
Ketoconazole
mediated
specifically
amplification,
requires
These
findings
highlight
potential
targets
intervention
combat
improve
outcomes.