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Current
Drug Targets
ISSN: 1389-4501
Current Drug Targets
Volume 6, Number 8, December 2005
Contents
Fungal Infections and Antifungal Strategies
Guest Editor: Karin Thevissen
Editorial Pp.847
Fungal Infections of the Skin: Infection Process and
Antimycotic Therapy Pp.849
M. Borgers, H. Degreef and G. Cauwenbergh
[Abstract]
Systemic Fungal Infections Caused by Candida Species:
Epidemiology, Infection Process and Virulence Attributes Pp.863
A.L. Mavor, S. Thewes and B. Hube
[Abstract]
Systemic Fungal Infections Caused by Aspergillus
Species: Epidemiology, Infection Process and Virulence
Determinants Pp.875
A.A. Brakhage
[Abstract]
Fungal Biofilms and Antimycotics Pp.887
J. Chandra, G. Zhou and M.A. Ghannoum
[Abstract]
Currently Used Antimycotics: Spectrum, Mode of Action
and Resistance Occurrence Pp.895
I.E.J.A. François, A.M. Aerts, B.P.A. Cammue and
K. Thevissen
[Abstract]
Fungal Pathogens Research: Novel and Improved Molecular Approaches
for the Discovery of Antifungal Drug Targets Pp.909
H. Tournu, J. Serneels and P. Van Dijck
[Abstract]
Fungal Sphingolipids as Targets for the Development
of Selective Antifungal Therapeutics Pp.923
K. Thevissen, I.E.J.A. François, A.M. Aerts and
B.P.A. Cammue
[Abstract]
Antifungal Susceptibility Testing Methods Pp.929
M.A. Pfaller
[Abstract]
Detection of Fungal Infections Using Radiolabeled Antifungal
Agents Pp.945
A. Lupetti, M.M. Welling, E.K.J. Pauwels and P.H. Nibbering
[Abstract]
Abstracts
[Back to top]
Editorial
The current review issue regarding 'Fungal Infections and
Antifungal Strategies' unites reviews regarding (i) the infection
process of pathogenic fungi resulting in topical or systemic
infections, (ii) fungal biofilms, (iii) currently used antimycotics,
(iv) novel antifungal drug targets, (v) antifungal susceptibility
testing methods and (vi) the use of radiolabeled antifungal
agents for early detection of fungal infections.
Fungal infections are categorized in two groups: topical
and systemic infections. Topical fungal infections affect
body surfaces and can be chronic, as discussed by Borgers
and coworkers. Systemic fungal infections can occur in an
organ or in the whole body and are transferred via
the bloodstream. Compared to other microbial infections, systemic
fungal infections are characterized by lower frequencies but
generally high mortality rates (40-100%). The most common
causes of these infections are Candida spp., as discussed
by Mavor and coworkers, and filamentous fungi such as Aspergillus
spp., as discussed by Brakhage. Several factors are associated
with the increasing incidence of fungal infections, including
the larger population of immunocompromized patients and the
increasing use of invasive devices and implants that can be
colonized by fungal biofilms. Biofilms are crucial for the
development of fungal infections as they can serve as a nidus
for disease. Moreover, surface attachment causes these fungal
cells to enter a special physiological state in which they
are highly resistant to most of the currently used antifungal
drugs, as discussed by Chandra and coworkers.
Since there are no fungal vaccines currently licensed, the
only clinical recourse to combat fungal infections is the
use of therapeutics. The currently used antifungal therapeutics
are prone to resistance and suffer from pharmacological limitations,
harmful drug-drug interactions, limited activity spectrum
and/or high general cytotoxicity, as discussed by François
and coworkers. Therefore, the search for new antifungal components
with a novel mode of action is imperative. Recent advances
in genetics and genome-based technologies will allow for the
identification and validation of new antifungal drug targets
to design novel target-based screening strategies, as discussed
by Tournu and coworkers and Thevissen and coworkers.
To drive this antifungal drug discovery process more efficiently,
novel in vitro assays that mimic in vivo fungal growth, thereby
more accurately predicting in vivo efficacy of antifungal
components, are mandatory. Current in vitro susceptibility
tests will be discussed by Pfaller.
An accurate and rapid diagnosis is a critical factor limiting
efficient antifungal therapy in immunocompromized patients.
Therefore, fast and localized diagnosis of a broad range of
pathogenic fungi is mandatory to efficiently combat fungal
infections. Given the limitations of the currently used PCR-
and ELISA-based methods, development of newer diagnostic techniques
are mandatory. A promising novel diagnostic technique is the
use of radiolabeled antifungals to monitor the in vivo distribution
of fungal infections in infected hosts by Single Photon Emission
Computerized Tomography or Positron Emission Tomography, as
discussed by Lupetti and coworkers.
In conclusion, it can be stated that the following developments
are needed to tackle the increasing problem of systemic fungal
infections and the lack of efficient antifungal therapeutics:
(i) the identification of novel types of antifungal components
with respect to their mode of action and fungal targets, (ii)
improved in vitro susceptibility testing methods and animal
models to more accurately evaluate in vivo efficacy
of these novel antifungals, and (iii) early and reliable detection
and localization of fungal infections in order to efficiently
target antifungal therapy.
Dr. Karin Thevissen
Guest Editor
Centre of Microbial and Plant Genetics
Katholieke Universiteit Leuven
Kasteelpark Arenberg 20
B-3001 Heverlee
Belgium
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Fungal Infections of the Skin: Infection Process and
Antimycotic Therapy
M. Borgers, H. Degreef and G. Cauwenbergh
Dermatomycoses are among the most widespread and common
superficial and cutaneous fungal infections in humans. These
typically nonfatal conditions are difficult to treat, especially
infections of the nail. Dermatomycoses are caused by filamentous
fungi such as Trichophyton, Microsporum or Epidermophyton
species. These filamentous fungi have a high affinity for
keratin, an important component of hair, skin and nails, which
are the primary areas of infection by dermatophytes. The antifungal
agents currently marketed for dermatomycoses are mainly inhibitors
of ergosterol bio-synthesis, except for griseofulvin, which
interferes with the cytoplasmic and nuclear microtubular system.
Three differ-ent types of inhibitors of the ergosterol biosynthetic
pathway have been proven to be effective in clinic: the azoles
(e.g. topical miconazole and topical/oral ketoconazole, itraconazole
and fluconazole), the allylamines (e.g. terbinafine) and morpholines
(amorolfine). Even today more effective antifungal azoles
with less adverse effects and short-term therapy are deemed
necessary to treat dermatophytosis. A promising novel triazole
compound in this respect is R126638, which showed potent in
vitro and in vivo activity.
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Systemic Fungal Infections Caused by Candida
Species: Epidemiology, Infection Process and Virulence Attributes
A.L. Mavor, S. Thewes and B. Hube
Candida species, in particular C. albicans,
represent a major threat to immunocompromised patients. Able
to exist as a commensal on mucosal surfaces of healthy individuals,
these opportunistic fungi frequently cause superficial infections
of mucosae and skin. Furthermore, in hospital settings,
Candida species may cause life-threatening invasive infections
in a growing population of vulnerable patients. In fact, candidaemia
is associated with the highest crude mortality of all bloodstream
infections. Candida cells may enter the bloodstream
by direct penetration from epithelial tissues, due to damage
of barriers in the body caused by surgery, polytrauma or drug
treatment, or may spread from biofilms produced on medical
devices. From the bloodstream, cells may infect almost all
organs but appear to prefer certain organs depending upon
the route of infection. The exact mechanisms by which Candida
cells survive the challenge of the blood environment
and escape from the bloodstream to cause deep-seated infections
have not yet been elucidated, but various investigations are
reviewed. It is clear, however, that Candida must
have particular attributes which enable the organism to survive
and grow within the environment of healthy individuals and
to invade tissues in the immuno-compromised host. Most studies
have focussed on C. albicans and this review will
therefore summarise work on the various known virulence factors
and methods used to identify further virulence attributes
of this fungus.
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Systemic Fungal Infections Caused by Aspergillus
Species: Epidemiology, Infection Process and Virulence Determinants
A.A. Brakhage
Infections with mould pathogens have emerged as an increasing
risk faced by patients under sustained immunosuppression.
Species of the Aspergillus family account for most
of these infections and in particular Aspergillus fumigatus
can be regarded as the most important airborne-pathogenic
fungus. The improvement in transplant medicine and the therapy
of hematological malignancies is often complicated by the
threat of invasive aspergillosis. Specific diagnostics are
still limited, as are the possibilities of therapeutic intervention.
Hence, invasive aspergillosis is still associated with a high
mortality rate that ranges from 30 % to 90 %. In recent years,
considerable progress has been made in understanding the genetics
of A. fumigatus and molecular techniques for the
manipulation of the fungus have been developed. Molecular
genetics offers not only approaches for the detailed characterization
of gene products that appear to be key components of the infection
process but also selection strategies that combine classical
genetics and molecular biology to identify virulence determinants
of A. fumigatus. The review discusses aspects of
the current knowledge of the in-fection process, mechanisms
of protection of the fungus against immune effector cells,
and virulence determinants of A. fumigatus.
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Fungal Biofilms and Antimycotics
J. Chandra, G. Zhou and M.A. Ghannoum
Device-related infections in most nosocomial diseases can
be traced to the formation of biofilms (microbial communities
encased within a polysaccharide-rich extracellular matrix)
by pathogens on surfaces of these devices. Candida
species are the most common causative agents of these infections,
and biofilms formed by these fungal organisms are associated
with drastically enhanced resistance against most antimicrobial
agents. This enhanced resistance contrib-utes to the persistence
of this fungus despite antifungal therapy. Recent studies
showed that Candida biofilms exhibit antifungal resistance
against most antifungal agents with the exception of echinocandins
and lipid formulations of AMB. This review discusses methods
used to evaluate biofilm resistance and provide information
on susceptibility pattern of candidal biofilm as well as studies
investigating the mechanisms underlying biofilm resistance.
[Back to top]
Currently Used Antimycotics: Spectrum, Mode of Action
and Resistance Occurrence
I.E.J.A. François, A.M. Aerts, B.P.A. Cammue and
K. Thevissen
The increasing incidence of fungal infections combined with
the emerging problem of antifungal drug resistance have prompted
investigations of the mode of action of the currently used
antifungal therapeutics (antimycotics). The routinely used
antimycotics can be grouped into six different classes based
on their mode of action. In this review, the mode of action
and antifungal spectrum of these classes are discussed, together
with possible resistance development against them.
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Fungal Pathogens Research: Novel and Improved Molecular
Approaches for the Discovery of Antifungal Drug Targets
H. Tournu, J. Serneels and P. Van Dijck
With the rise of fungal infection incidence amongst the
patient population, the importance of developing new antifungal
drug targets is higher than ever. This review mainly focuses
on the three most prevalent fungal pathogens, Candida,
Aspergillus and Cryptococcus, and on the most
recent progresses in molecular research that contribute to
a better understanding of the pathogen itself, but also its
host and the interaction with its host. We consider the progress
made in comparative genomics following the huge effort of
fungal genome sequence projects undertaken in the last few
years. We focus not only on currently used mammalian animal
models such as mice, but also on novel non-mammalian models,
such as the nematode worm Caenorhabditis elegans
and the fruit fly Drosophila melanogaster, which
offer useful tools in the area of the innate immune response
to fungal infections. In addition we relate to the recent
genomic and proteomic studies and focus on the use of these
approaches in in vivo experiments in the pathogen
itself as well as in the host. Finally, we describe the latest
targeted mutagenesis strategy available in C. albicans
and the use of RNA interference in both Cryptococcus neoformans
and A. fumigatus. Our aim is not to give an exhaustive
list of all new strategies but rather to give an overview
of what will contribute most to the identification of new
antifungal drug targets and the establishment of novel antifungal
strategies.
[Back to top]
Fungal Sphingolipids as Targets for the Development
of Selective Antifungal Therapeutics
K. Thevissen, I.E.J.A. François, A.M. Aerts and
B.P.A. Cammue
Sphingolipids are essential membrane components, present
in all eukaryotic cells, but structurally distinct in mammalian
and fungal cells. Therefore, they represent an attractive
new target for the development of novel antimycot-ics. This
review will briefly highlight sphingolipid biosynthesis and
functions in the yeast Saccharomyces cerevisiae.
In addition, naturally occurring antifungal compounds that
interact with fungal-specific sphingolipids, resulting in
fungal growth arrest, will be discussed regarding their mode
of action, and therapeutic value. These compounds include
plant and insect defensins, syringomycin E and antifungal
antibodies to sphingolipids.
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Antifungal Susceptibility Testing Methods
M.A. Pfaller
The number of systemically active antifungal agents has
increased dramatically in recent years in response to the
challenge of invasive mycoses. Additional work is needed to
better understand the mechanisms of action of these agents
as well as the mechanisms of resistance expressed by the fungal
pathogens. Antifungal susceptibility testing has been standardized
and refined and now may be considered to play an important
role in the management of invasive mycoses. More work is needed
to optimize the methods for testing new antifungal agents
and for testing pathogens other than Candida. The
ongoing efforts and international collaborations designed
to address these issues will provide important information
that will improve the management of serious fungal infections.
[Back to top]
Detection of Fungal Infections Using Radiolabeled
Antifungal Agents
A. Lupetti, M.M. Welling, E.K.J. Pauwels and P.H. Nibbering
The outcome of antifungal therapy depends on the progression
of the infection at the start of therapy. Unfortunately, most
patients are diagnosed once the fungal infection has progressed
considerably as a result of the non-specific clinical signs
of fungal infections in immunocompromised patients and the
poor sensitivity of current mycological diagnostic tests.
This review will highlight current fungal diagnostic techniques
and will focus on scintigraphic methods for the specific detection
of fungal infections in mice. For this purpose, antifungal
components (e.g. fluconazole and antifungal peptides) are
radiolabeled e.g. with technetium-99m (99mTc) and
their in vivo distribution is monitored in infected
mice. It has been demonstrated that 99mTc-fluconazole
is an excellent tracer to detect Candida albicans
infections in mice as it distinguishes these infections from
bacterial infections and sterile inflammations. However, this
radiopharmaceutical only poorly detects infections with Aspergillus
fumigatus in mice. 99mTc-peptides derived
from antifungal peptides/proteins, such as human ubiquicidin
and lactoferrin, can distinguish C. albicans and
A. fumigatus infections from sterile inflammations,
but not from bacterial infections, in mice. Furthermore, the
efficacy of fluconazole in C. albicans-infected mice
could be successfully monitored using 99mTc-ubiquicidin.
In conclusion, neither 99mTc-fluconazole nor the
99mTc-peptides tested are optimal tracers for fungal
infections. Nonetheless, since early initiation of antifungal
therapy for candidemia reduces its high mortality rate, a
positive result with 99mTc-fluconazole scintigraphy
is of clinical relevance. Finally, the possibility that other
(radiolabeled) antifungal agents, e.g. voriconazole, caspofungin,
antifungal plant or insect defensins, can be useful for detection
of fungal infections should be considered.
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