Mechanisms of Azole Potentiation: Insights from Drug Repurposing Approaches
ACS Infectious Diseases,
Год журнала:
2025,
Номер
unknown
Опубликована: Янв. 3, 2025
The
emergence
of
azole
resistance
and
tolerance
in
pathogenic
fungi
has
emerged
as
a
significant
public
health
concern,
emphasizing
the
urgency
for
innovative
strategies
to
bolster
efficacy
azole-based
treatments.
Drug
repurposing
stands
promising
practical
avenue
advancing
antifungal
therapy,
with
potential
swift
clinical
translation.
This
review
offers
comprehensive
overview
synergistic
agents
uncovered
through
drug
strategies,
alongside
an
in-depth
exploration
mechanisms
by
which
these
augment
potency.
Drawing
from
mechanisms,
we
delineate
aimed
at
enhancing
effectiveness,
such
inhibiting
efflux
pumps
elevate
concentrations
within
fungal
cells,
intensifying
ergosterol
synthesis
inhibition,
mitigating
cell
azoles,
disrupting
biological
processes
extending
beyond
synthesis.
is
beneficial
development
potentiators,
it
meticulously
examines
instances
provides
nuanced
discussions
on
underlying
progression
potentiators
strategies.
Язык: Английский
Otilonium Bromide Exhibits Potent Antifungal Effects by Blocking Ergosterol Plasma Membrane Localization and Triggering Cytotoxic Autophagy in Candida Albicans
Advanced Science,
Год журнала:
2024,
Номер
unknown
Опубликована: Июль 12, 2024
Abstract
Candidiasis,
which
presents
a
substantial
risk
to
human
well‐being,
is
frequently
treated
with
azoles.
However,
drug‐drug
interactions
caused
by
azoles
inhibiting
the
CYP3A4
enzyme,
together
increasing
resistance
of
Candida
species
azoles,
represent
serious
issues
this
class
drug,
making
it
imperative
develop
innovative
antifungal
drugs
tackle
growing
clinical
challenge.
A
drug
repurposing
approach
used
examine
library
Food
and
Drug
Administration
(FDA)‐approved
drugs,
ultimately
identifying
otilonium
bromide
(OTB)
as
an
exceptionally
encouraging
agent.
Mechanistically,
OTB
impairs
vesicle‐mediated
trafficking
targeting
Sec31,
thereby
impeding
plasma
membrane
(PM)
localization
ergosterol
transporters,
such
Sip3.
Consequently,
obstructs
movement
across
membranes
triggers
cytotoxic
autophagy.
It
noteworthy
that
C.
albicans
encounters
challenges
in
developing
because
not
substrate
for
transporters.
This
study
opens
new
door
therapy,
wherein
disrupts
subcellular
distribution
induces
Additionally,
circumvents
hepatotoxicity
associated
azole‐mediated
liver
enzyme
inhibition
avoids
export‐mediated
.
Язык: Английский
Integrating ensemble machine learning and multi-omics approaches to identify Dp44mT as a novel anti-Candida albicans agent targeting cellular iron homeostasis
Xiaowei Chai,
Yuanying Jiang,
Hui Lü
и другие.
Frontiers in Pharmacology,
Год журнала:
2025,
Номер
16
Опубликована: Апрель 24, 2025
Candidiasis,
mainly
caused
by
Candida
albicans,
poses
a
serious
threat
to
human
health.
The
escalating
drug
resistance
in
C.
albicans
and
the
limited
antifungal
options
highlight
critical
need
for
novel
therapeutic
strategies.
We
evaluated
12
machine
learning
models
on
self-constructed
dataset
with
known
anti-C.
activity.
Based
their
performance,
optimal
model
was
selected
screen
our
separate
in-house
compound
library
unknown
activity
potential
agents.
of
compounds
confirmed
through
vitro
susceptibility
assays,
hyphal
growth
biofilm
formation
assays.
Through
transcriptomics,
proteomics,
iron
rescue
experiments,
CTC
staining,
JC-1
DAPI
molecular
docking,
dynamics
simulations,
we
elucidated
mechanism
underlying
compound.
Among
models,
best
predictive
an
ensemble
constructed
from
Random
Forests
Categorical
Boosting
using
soft
voting.
It
predicts
that
Dp44mT
exhibits
potent
tests
further
verified
this
finding
can
inhibit
planktonic
growth,
formation,
albicans.
Mechanistically,
exerts
disrupting
cellular
homeostasis,
leading
collapse
mitochondrial
membrane
ultimately
causing
apoptosis.
This
study
presents
practical
approach
predicting
com-pounds
provides
new
insights
into
development
homeostasis
Язык: Английский