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Vol. 26. Núm. 1.
Páginas 15-22 (Marzo 2009)
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Vol. 26. Núm. 1.
Páginas 15-22 (Marzo 2009)
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Nuevos antifúngicos, nuevas dianas y estrategias terapéuticas para el tratamiento de las micosis invasoras: revisión de la bibliografía (2005-2009)
Novel antifungal agents, targets or therapeutic strategies for the treatment of invasive fungal diseases: a review of the literature (2005-2009)
Ana Espinel-Ingroffa
a VCU Medical Center, Richmond, VA, USA
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Table 1. New antifungal agents, targets, strategies (2005-2009)
Antecedentes: La incidencia y la prevalencia de micosis invasoras continúa siendo un problema de salud pública. A pesar de los tratamientos más agresivos con los nuevos fármacos o los antifúngicos más establecidos, las infecciones fúngicas causan bastante mortalidad y morbilidad, especialmente en los pacientes inmunodeficientes. Objetivos: Revisar críticamente la bibliografía acerca de los nuevos desarrollos más importantes en el campo del tratamiento antifúngico en las versiones en español y en inglés. Métodos: Se enfocó la revisión en los estudios relacionados a dianas o mecanismos de acción diferentes a los actuales; también se revisaron los informes de fármacos nuevos, estrategias terapéuticas prometedoras o alternativas para los pacientes que presentan infecciones fúngicas invasoras. Resultados: En numerosos estudios se ha evaluado una variedad de factores de virulencia como posibles dianas de actividad antifúngica. Más recientemente, la relación química-genética de los antifúngicos aprobados y de otras moléculas se ha definido debido a la identificación de los genes relacionados con el mecanismo de acción correspondiente. Conclusiones: A pesar de los resultados favorables aportados en esos estudios, el desarrollo de la mayoría de estas moléculas está al nivel de su espectro in vitro o in vivo, pero en estudios de eficacia en modelos animales. Por lo tanto, deben realizarse más evaluaciones para que su desarrollo llegue al nivel de ensayos clínicos.
Palabras clave:
Antifungal concentrations monitoring
Genetic studies
New antifungal activity targets
New antifungal therapy strategies
Novel antifungal agents
Background: The incidence and prevalence of serious mycoses continues to be a public health problem. Despite aggressive treatment with new or more established licensed antifungal agents, these infections are an important cause of morbidity and mortality, especially in immunocompromised patients. Aims: To critically review the literature regarding important new developments in the field of antifungal therapy both in the English and Spanish versions. Methods: The search of the literature focused on different antifungal targets or mechanisms of action as well as new agents or strategies that could improve antifungal therapy. Results: The review produced a huge amount of information on the use of virulent factors such as growth, filamentation, pathogen tissue clearance, among others, as putative targets of antifungal activity. More recently, the chemical-genetic relationships for licensed agents as well as for other compounds have been provided by the identification of the genes related to the mechanism of action. Conclusions: Although the antifungal activity of numerous compounds has been examined, most of them are at the in vitro or animal models of efficacy stages. Therefore, further investigation should be carried out to realize the true clinical utility of these compounds. © 2009 Revista Iberoamericana de Micología. Published by Elsevier España, S.L. All rights reserved.
Concentraciones antif¨²ngicas
Estudios gen¨¦ticos
Nuevas dianas antifúngicas
Nuevas estrategias terapéuticas antifúngicas
Nuevos antifúngicos
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The incidence and prevalence of invasive fungal infections have increased since the 1980s, especially in the large population of immunocompromised patients and/or those hospitalized with serious underlying diseases7,24. In addition, the mortality and morbidity of these infections is quite substantial. The most common fungal pathogens continue to be the species of Candida and Aspergillus7,54,86,91. Parallel to the increase in fungal infections, two triazoles (voriconazole and posaconazole) and three echinocandins (anidulafungin, caspofungin and micafungin) have been licensed for the treatment and prevention of these infections4-6.

The echinocandins have a unique mechanism of action (inhibition of β-1,3-D-glucan synthase) and a broad and similar spectrum of in vitro activity against Candida spp. and Aspergillus spp.25,66,85. During the last few years, mechanisms of resistance to most licensed agents in Candida spp., and to a certain point in Aspergillus spp., have been elucidated25,46,83. Although resistance of common Candida spp. and Aspergillus spp. to echinocandins and azoles is rare, it has been documented and continues to be reported8,25,29,46,83. The mortality rates associated with invasive candidiasis are approximately 0.4 deaths per 100,000 population/year while there was a decrease with aspergillosis from 0.42 per 100,000 in 1997 to 0.25 per 100,000 in 2003 in the United States86. Although it is hoped that the introduction of these new agents will improve these rates, the mortality rate in most aspergillosis studies is about 50%. Therefore, there is a need for new targets or strategies in antifungal therapy. This review summarizes some of the new developments and/or discoveries found in the literature since 2005 (Table 1).

Antifungal agents under development

New polyene and other agents

The lipopeptide micafungin (8, FK463)103, like the other echinocandins, has fewer side effects than amphotericin B and other agents, but the echinocandins have not been approved as the first line therapy for invasive aspergillosis. The novel polyene SPK-843 showed less renal toxicity than both amphotericin B or liposomal amphotericin B and also better activity than micafungin and both established polyenes in a murine model of pulmonary aspergillosis45. Clinical trials are presently being conducted. Preclinical in vitro and in vivoevaluations of the novel arylamidine T-2307 indicate that this agent has potential for the treatment of candidiasis, cryptococcosis and aspergillosis. The mechanism of action of T-2307 is not yet established, but it has been suggested that it is associated with the mitochondrial function of the fungal cell68. These preliminary results support the continued development of these compounds.

An ambruticin analog (a cyclopropyl-pyran acid which interferes with the osmoregulatory system) was effective in both murine models of coccidioidomycosis94 and pulmonary aspergillosis19, but no further information was found in the literature since 2006.

New triazole

Voriconazole has no activity against the mucoraceous. The new triazole isavuconazole, (BAL4815) in late state clinical development for the treatment of aspergillosis, appears to have in vitro activity against the zygomycetes (MIC50 and MIC100 of 1 and 2 μg/ml, respectively) versus voriconazole MICs of ≥ 16 μg/ml32; also, its activity was superior to that of both itraconazole and voriconazole against Candida spp.92. However, contradictory results have been documented for the zygomycetes in other studies (MICs50 of > 6 μg/ml)60,82.


Icofungipen (PLD-118, BAY 10-8888) is a derivative of cispentacin. It is a beta amino acid that targets isoleucyl-t-RNA synthetase; intracellular inhibitory concentrations at the target site are achieved by its active accumulation in susceptible fungal cells. Although its in vitro activity against Candida albicans is poor, it has shown strong in vivo activity in a neutropenic rabbit model for disseminated candidiasis, including the treatment of central nervous system infection36,84. It has dose-dependent pharmacokinetics and it shows potential for the treatment of invasive candidiasis.

Inhibitor ofβ-1,6-glucan synthesis

75-4590, a pyridobenzimidazole, is a specific inhibitor of β-1,6-glucan synthase; it has shown activity against Candida spp. and appears to inhibit hyphal elongation of C. albicans50. Genetic analysis of a resistant mutant of Saccharomyces cerevisiae indicated that its primary target was Kre6p (a β-1,6-glucan synthase)70. Its growth inhibition is dose-dependent; since Kre6p homologous have been found in Aspergillus fumigatus, partial silencing of KRE6P expression makes A. fumigatus more susceptible to Congo red which appears to indicate the role of Kre6p in cell wall construction37.

Monoclonal antibody therapy

Patient therapy

Casadevall13 considers serum therapy the third age of antimicrobial therapy. In 2006, Pachl et al77 reported the results of the combination of amphotericin B and Mycograb (Neutec Pharma), a human recombinant monoclonal antibody as an inhibitor of heat shock protein 90, in patients with invasive candidiasis. An 84% overall response was observed by day 10 in the combined therapy versus 48% in patients treated with amphotericin B alone; clinical and mycological response, Candida-attributable mortality and rate of culture-confirmed sterilization were also superior with the combined therapy. The first application of monoclonal antibody therapy for a fungal disease in humans was the evaluation of the murine-derived anticryptococcal antibody 18B7 for cryptococcal meningitis by Larsen et al53. Their promising results support further evaluation of 18B7.

Animal models in vitro

The monoclonal antibody Mab C7 has been shown to inhibit the adhesion and germination of C. albicans and has direct candidacidal activity75. The use of microbe-specific monoclonal antibodies as delivery vehicles for targeting biofilms with cytocidal radiation was successfully evaluated by Martinez et al61; they found that Cryptococcus neoformans biofilms were susceptible to this treatment, which could be a novel option for either the prevention or treatment of bio-films. More recently, the combination of caspofungin and efungumab, a human antibody fragment, was used against the heat shock protein 90, a target of the human response in invasive candidiasis39; these preliminary results indicate that efungumab enhanced the activity of caspofungin in the animal model. Similar results were obtained by Mattila et al63 in an immunosuppressed murine model of invasive pulmonary A. fumigatus infection when animals were treated with Dectin-1 Fc via beta-glucan recognition and opsonic elimination; the conclusion was that Dectin-1 Fc could serve as a prophylactic treatment of this infection.

Strategies for the treatment of biofilms

C. albicans biofilms are intrinsically resistant to most antifungal agents. The optimal efficacies of caspofungin and micafungin were evaluated using anin vitro model of C. albicans biofilm14. Caspofungin (2 mg/ml) and micafungin (5 mg/ml) could be good candidates for the reduction or control of fungal biofilms associated with silicone medical devices, as part of the antifungal lock. Both echinocandins were able to significantly and persistently reduce the yeast metabolic activity of intermediate and mature biofilms, 12 h and 5 days old, respectively, when used as catheter lock solutions. The in vitroactivity of terpenes21 and baicalein12 has also been evaluated against C. albicans biofilms and they appear to be promising candidates to either treat or reduce the incidence of device-associated infections. The cells treated with baicalein expressed lower levels of mRNA than the cells grown in its absence12.


Antifungal drug-drug combinations

The echinocandins do not have any activity against C. neoformans. The in vitro interactions of micafungin with either amphotericin B, fluconazole, itraconazole or voriconazole were evaluated for different Cryptococcus spp.; no antagonism was observed and synergy was frequently observed with the combination of micafungin and amphotericin B93; similar results were observed in experimental aspergillosis23 with the same combination and more recently, against simulated Candida endocarditis vegetations with the combination of micafungin and flucytosine79. More research is needed regarding the combinations of echinocandins with triazoles and lipid formulations in randomized clinical trials. Although the combination of caspofungin with these latter agents has provided mostly favorable results, they were not obtained in randomized clinical trials113.

Antifungal drug combination with other agents

The combination of the statin lovastatin and voriconazole was synergistic both in vitro and in vivo in a fly Drosophila melanogastermodel of zygomycosis16. More recently, favorable in vitro data has been reported for retigeric acid either alone or in combination with azoles against C. albicans98. Steinbach et al97 demonstrated, using a calcineurin A mutant (cnaA), that calcineurin is critical for A. fumigatus hyphal growth, tissue invasion and pathogenicity and enhanced the antifungal activity of cell wall inhibitors such as caspofungin or nikkomycin. EDTA, a lead poisoning chelator therapeutic that appears to have antifungal activity, was shown to have synergistic activity in combination with amphotericin B lipid complex in a rat model of immunosuppressed A. fumigatus invasive pulmonary aspergillosis35. The clinical significance of these observations is yet to be determined.

Pharmacokinetic studies

A pharmacokinetic study was conducted to determine the maximal tolerated dose of micafungin, and especially the pharmacokinetic profile when micafungin was combined with fluconazole in cancer patients undergoing either bone marrow or peripheral stem cell transplants38. This combination was found to be safe and the maximal tolerated dose of micafungin was not reached at 200 mg/ day for four weeks. Keirns et al49 reported that voriconazole did not affect the pharmacokinetics of micafungin; however, an absence of drug interaction was observed in healthy adults. These are promising results, but data from patients are needed.

Drug monitoring, pharmacodynamics and pharmacokinetic strategies

Drug monitoring

Therapeutic monitoring is essential to ensure drug exposure (dosage increase when it is possible) or to avoid toxicity (administer lower doses) during the antifungal treatment of invasive mycoses. Monitoring of voriconazole serum concentrations is important due to the frequent inter-subject variability (trough concentrations of <0.1 to about 10 μg/ml from patients taking 200 mg twice a day)96. There was a 90% response to voriconazole therapy when serum levels were >1 μg/ml, but only 54% when the serum concentrations were lower in patients with invasive candidiasis or aspergillosis80. Based on those results, the paucity of voriconazole MIC data for Histoplasma capsulatum, the lack of prospective trials to establish the effectiveness of this agent for histoplasmosis treatment and the wide range of voriconazole serum concentrations (<2.05 to<0.125 μg/ml) also found in their study, Freifeld et al28 have recommended measuring trough levels in patients receiving voriconazole for histoplasmosis. As there is also inter-subjective variability of itraconazole and posaconazole serum concentrations, drug monitoring of these triazoles also could be useful3. Maximal organism killing has correlated with flucytosine concentrations above the MIC in animal models3,41. In addition, high flucytosine levels have correlated with toxicity and elevated voriconazole concentrations with encephalopathy3,80.

Pharmacodynamics and pharmacokinetics

Pharmacodynamic results indicated that the current clinical dosing regimens of micafungin were appropriate for the treatment of infections caused by both C. albicans and Candida glabrata; micafungin exposures needed for efficacy were similar2. Relating the results in the murine neutropenic candidiasis model to human micafungin pharmacokinetics for the 100 mg/day dosing regimen would predict an inhibitory pharmacodynamic target against both species with MICs up to 0.06 μg/ml. In addition, the free drug micafungin exposures required to produce stasis and killing endpoints were similar to those reported for anidulafungin against C. albicans and C. glabrata2. Other strategies regarding dosing regimen adjustment to improve micafungin efficacy also have been examined in a murine neutropenic model of candidiasis33 and in patients76. Furthermore, population studies have provided real inter-patient (pediatric and adult) pharmacokinetic variability34,40.

Serum effect on antifungal activity

Serum-MICs of both caspofungin and micafungin for C. albicans were better predictors of in vivo potency than conventional MICs (hyphal growth inhibition or C. albicans kidney burden measurement)59. These results were confirmed recently by the reports of the influence of serum in drug protein binding. Using in vitro growth assays, it has been reported that protein binding shifted the antifungal activity of echinocandins against Aspergillus spp. and Candida spp. resulting in nearly equivalent MICs or MECs78; serum decreased the sensitivity of glucan synthase to echinocandins. Because of that, it has been suggested that the susceptible breakpoint established by the Clinical and Laboratory Standards Institute of ≥ 2 μg/ml does not apply to the three echinocandins, but only to caspofungin. Using fks1 mutants, Garcia-Effron et al30 have demonstrated that serum MICs captured all (100%) fks1 mutants above the MIC breakpoint, but this breakpoint was less applicable for anidulafungin and micafungin. Micafungin or anidulafungin MICs it should be equal or greater than 0.5 μg/ml provided similar results (95% of the mutant isolates were captured). Their recommendation was to either lower the breakpoint or to use caspofungin in vitro data as a surrogate marker to identify echinocandin resistance, since the three echinocandins have similar activity target, resistance mechanisms, spectrum and in vitro potency; the use of surrogates has been previously suggested for the triazoles, where fluconazole breakpoints can be used to assess patterns of susceptibility of other triazoles.


Further of research has been dedicated to the investigation of the antifungal activity of a variety of peptides mostly against C. albicans, A. fumigatus and C. neoformans. Although they are promising leads for the development of new agents, a great deal of investigation is needed to determine their clinical usefulness. Some of the developments in this area are summarized below.

Activity against C. albicansand C. neoformans

Inhibition of the transformation from budding to hyphal or pseudohyphae formation, an important virulent factor in C. albicans, has been observed with the galanin message-associated peptide (GMAP)87, amentoflavone44 and a lactoferrin-derived peptide58; lactoferrin activity was dose-dependent and it was effective in disseminated murine candidiasis

The histatins have potential as antifungal agents since they are the first line of defense against infection with oral candidiasis. Zhu et al114 synthesized a four-branched histidine (H2K4b) that affected the growth of several species of Candida by pH buffering followed by endosomal-disruption. Since this molecule accumulated efficiently in C. albicans, it may indicate its ability to transport other antifungal agents. Histatin resistant derivatives of C. albicans had the same killing mechanism as the parent strain, but they had different proteins than those found in the parent cell; the most important of those differences was the absence in the resistant derivatives of the elongation factor 2 (Ef2), a specific target for the antifungal sordarin. There was also a decrease in the transcript level of the potassium transporter encoded by TRK1, a critical mediator of histatin killing. These results indicate that there may be several intracellular targets for histatin 3 in C. albicans26. Among at least 50 histatin peptides derived from posttranslational proteolytic processing, histatin 5 (Hst 5) has shown the highest level of activity against C. albicans. Its mechanism of action involved, first binding to the cell wall protein Ssa2 of C. albicans, followed by translocation to intracellular targets. Jang et al42 demonstrated that binding and transportation were independent events and that the P-113 fragment of Hst 5 required a specific peptide sequence for translocation.

Cathelicidin peptides were shown to have killing activity against C. albicans and C. neoformans that was associated with membrane permeabilization, but they had little activity against moulds9. However, the porcine 1905-Da cationic proline-rich peptide (SP-B) has shown activity against both yeast species and also A.fumigatus10. Recently, it was demonstrated that the fungicidal activity of the bass peptide derivative piscidin 2 (P2) was based on the formation of pores in the fungal membrane100.

Several investigators have focused their research on the adhesion and penetration of C. albicans in tissues. Foldvari et al27 demonstrated in a rat model of oral candidiasis that Fimbrigal-P (an antiadhesion synthetic carbohydrate) reduced fungal burden and was a promising antifungal agent for the prevention and treatment of infections when the target was β-GaINac(1-4)-β-alactosidase disaccharide. The surfactant-coated cationic nanoparticles and lipids are potential prophylactics that act by priming the buccal epithelial cells against fungal adhesion and infection64,105. The activity of two flavonoid compounds (apigenin and kaempferol), the indole alkaloids ibogaine and berberine were evaluated as potential inhibitors of the virulent factors responsible for the penetration of C. albicans into human cells; they appeared to inhibit adherence and had aspartyl proteinase activity. The application of these compounds in cutaneous infection was shown to suppress symptoms and accelerated the elimination of the pathogen from the infection site111.

The human beta-defensins HBD-1 to HBD-3 and their analogs phd1 to phd-3 have shown fungicidal activity against C. albicans. Although the mechanism of action is not yet understood (the initial site of action is the fungal membrane), both analogs may be potential antifungal therapeutic agents51. A plant defensin (RsAFP2), not toxic to mammalian cells, has been found to be prophylactically effective against murine candidiasis101. Active research continues regarding the characterization of other defensins as possible antifungal agents1,55,67.

It was demonstrated that the susceptibility to oligopeptides and amino acids was enhanced in C. albicans over expressing Cdr1p and Cdr2p, which resulted in higher uptake rates of these peptides via oligopeptide permeases106.

Activity against A. fumigatusand other moulds

Vallon-Eberhard et al104 have described that the ultra-short lipopeptide, palmitoyl-lys-ala-Dala-Lys (linked to fatty acids) was superior to amphotericin B in an immunosuppressed murine model of invasive pulmonary aspergillosis by A. fumigatus, which highlighted the potential of this family of lipopeptides as antifungal agents. Although enough data are not available regarding its mechanisms of action, it was suggested that the activity is membranolytic (detergent-like effect), similar to that of other enzyme inhibitors, e.g., echinocandins. Yu et al112 reported the antifungal activity of a heat-stable antifungal factor (HSAF) against a variety of fungal pathogens; its target is the disruption of the biosynthesis of sphingolipids, essential but different components of fungal and mammal cells. ThePenicillium chrysogenum antifungal protein (PAF) elicited hyperpolarization of the plasma membrane and the activation of ion channels62. The small hexapeptide PAF26 altered hyphal morphology (polar growth and branching), chitin deposition and caused other detrimental effects69; this peptide had preferential activity against moulds. Conidial germination of Aspergillus spp. and other moulds was shown to be inhibited by xanthorrhizol89 and lectin73.

A drosomycin-like defensin (DLD), a human homologue of drosomycin from the fly D. melanogaster, showed specific antifungal activity against filamentous fungi. Both an immunoregulatory effect on Aspergillus-stimulated cytokine production and the expression of DLD mRNA in mostly skin human tissues were observed, which is consistent with its putative role as a defensin against invading microorganisms95.

Enzyme inhibitors

Synthases and other enzymatic targets

Other possible antifungal agents are the synthase inhibitors such as pleofungins (inositol phosphorylceramide)109, N-alkyl derivatives that inhibit glucosamine-6p synthase65, elastase inhibitor from A. flavus (AFLEI) in combination with other existent licensed agents74, the GMP synthase inhibitors in C. albicans and A. fumigatus88 and the inhibition of mRNA polyadenosine polymerase43,81 by the natural products parnafungins; these inhibitors deserve further investigation for potential clinical use.

Chitin synthase inhibitors

The cell wall components chitinases are essential for cell wall plasticity during growth. Recently, the in vitro antifungal activity of the acidic mammalian chitinase against C. albicans and A. fumigatuswas demonstrated; efficient hydrolysis of chitin was observed18. These results confirmed earlier observations regarding the antifungal in vitro activity against a variety of fungal pathogens of other natural chitin synthase inhibitors such as sesquiterpene furan compound C-J-01110, O-methyl pisiferic acid and 8,20-dihydroxy-9(11),13-abietadien-12-one and 2'-benzoyloxycinnamaldehyde47,48.


Other possible targets for drug development are the phospholipase inhibitors; inhibition of C. neoformans by bisquaternary ammonium salts correlated with the inhibition of cryptococcal phospholipase B1 (PLB1, a newly identified virulent factor); C. albicans was also inhibited72. On the other hand, Widmer et al107 found that miltefosine delayed C. neoformans infection and mortality and reduced brain burden in a murine model of cryptococcosis; however, the relatively low inhibitory effect on the phospholipase B1 enzyme at concentrations exceeding the MIC by 2 to 20 times suggested that there was another mechanism involved in addition to phospholipase inhibition.

Other targets

Disruption of cytochrome biosynthesis which could induce apoptosis by coumarin derivatives in C. albicans102 and the candidacidal activity of Indol-3-carbinol by binding fungal DNA99 are two different mechanisms of action. Cruentaren has shown an inhibitory effect on mitochondrial ATPase activity as well as the growth of some yeasts and moulds52. Chamilos et al15 have shown that caspofungin MICs were lower when the C. parapsilosis mitochondrial respiratory pathway was inhibited; therefore this pathway could be responsible for the decreased susceptibility of this species to caspofungin and other echinocandins.

Fatty acids

The antifungal activity of fatty acids has been recognized for years. Although some of them are used as topical over-the-counter formulations, several fatty acids were evaluated between 2006 and 2008 for either topical use (6-acetylenic acids)56 or for the treatment of more invasive mycoses, e.g., (+/-)-2-methoxy-4-thiatetradecanoic and (+/-)-2- hydroxyl-4-thiatetradecanoic acids blocked the beta-oxidation pathway of C. albicans andC. neoformans11, and whey-derived free fatty acids20 and lavender oil22 inhibited germination or hyphal elongation of C. albicans.

Discovery of antifungal targets by genetic studies

The application of chemically induced haplo-insufficiency (growth phenotypes associated with the loss or deletion of function) has been used to screen for genes involved in the hyphal growth of C. albicans108, as well as to investigate fungal viability and virulence of other species; this type of research has led to the discovery of many putative antifungal targets.

Saville et al90 genetically engineered a C. albicans tet-NRG1 strain in which they could modulate filamentation and virulence by the presence or absence of doxycycline. They were able to confirm that this species can only cause disease when filamentation was induced with doxycycline. Doxycycline removal led to increased survival; mortality rates also increased markedly the longer the intervention was delayed. It was concluded that filamentation inhibition could be targeted to treat disseminated candidiasis.

Chitotriosidase, which is secreted by human macrophages, has been associated with the defense against chitin-bearing pathogens. The engineered cells (gene transfer of the chitotriosidase gene into Chinese hamster ovary cells) inhibited growth in vitro of Aspergillus niger, C. albicans and C. neoformans and increased longevity in a murine model of C. neoformans31. This effect was possible by the prolonged delivery of recombinant chitotriosidase.

Nazi et al71 identified the MET2gene (required for virulence) of C. neoformans H99 that encoded HTA (homoserine transacetylase) by complementation of an Escherichia colimetA mutant that lacks the gene encoding homoserine trans-succinylase (HTS). By screening a 1,000-compound library for HTA inhibitors, the first antifungal inhibitor of HTA was identified; this identification validated the use of fungal HTA as a potential target of new antifungal agents.

Using a genome comparison tool, Liu et al57 identified 240 conserved genes as possible antifungal targets in ten fungal genomes; essential genes in C. albicans were then identified by a repressible MET3 promoter system. When the expression of the C. albicansERG-1target was reduced via down-regulation of the MET3 promoter, the mutant became hypersensitive to its terbinafine inhibitor. Antifungal target candidates can be screened by this process.

It has been reported that fluconazole potency against C. neoformans was enhanced and became fungicidal when the expression of the genes (FAS1 or FAS2) that encoded C. neoformans fatty acid synthase was suppressed17; these observations indicated that fatty acids were essential for C. neoformans in vitro and in vivo growth. Therefore, FAS1 and FAS2 can potentially be fungicidal targets for C. neoformanseither alone or combined with azoles. Again further development is needed.


Although much progress has been accomplished towards the identification and understanding of putative targets or mechanisms of action that could lead to the development of new and improved antifungal agents, the usefulness of these compounds can only be assessed in randomized clinical trials.

Author's disclosure

The author has nothing to declare.

Correo electrónico: avingrof@vcu.edu; avingrof@verizon.net

Historia del artículo:

Recibido el 5 de febrero de 2009

Aceptado el 11 de febrero de 2009
Aerts AM, Francois IE, Meert EM, Li QT, Cammue BP, Thevissen K..
The antifungal activity of RsAFP2, a plant defensin from raphanus sativus, involves the induction of reactive oxygen species in Candida albicans..
J Mol Microbiol Biotechnol, 13 (2007), pp. 243-247
Andes DR, Diekema DJ, Pfaller MA, Marchillo K, Bohrmueller J..
In vivo pharmaco-dynamic target investigation for micafungin against Candida albicans and C. glabrata in a neutropenic murine candidiasis model..
Antimicrob Agents Chemother, 52 (2008), pp. 3497-3503
Andes D, Pascual A, Marchetti O..
Antifungal therapeutic drug monitoring: established and emerging indications..
Antimicrob Agents Chemother, 53 (2009), pp. 24-34
Antimicrobial Agents and Chemotherapy..
New antimicrobial agents approved by the U.S. food and drug administration in 2004 and new indications for previously approved agents..
Antimicrob Agents Chemother, 49 (2005), pp. 2151
Antimicrobial Agents and Chemotherapy..
New antimicrobial agents approved by the U.S. food and drug administration in 2005 and new indications for previously approved agents..
Antimicrob Agents Chemother, 50 (2006), pp. 1912
Antimicrobial Agents and Chemotherapy..
New antimicrobial agents approved by the U.S. food and drug administration in 2006 and new indications for previously approved agents..
Antimicrob Agents Chemother, 51 (2007), pp. 2649
Arendrup MC, Fuursted K, Gahrn-Hansen B, Jensen IM, Knudsen JD, Lundgren B, Schonheyder HC, Tvede M..
Seminational surveillance of fungemia in Denmark: notably high rates of fungemia and numbers of isolates with reduced azole susceptibility..
J Clin Microbiol, 43 (2005), pp. 4434-4440
Arendrup MC, Perkhofer S, Howard SJ, Garcia-Effron G, Vishukumar A, Perlin D, Lass-Florl C..
Establishing in vitro-in vivo correlations for Aspergillus fumigatus: the challenge of azoles versus echinocandins..
Antimicrob Agents Chemother, 52 (2008), pp. 3504-3511
Benincasa M, Scocchi M, Pacor S, Tossi A, Nobili D, Basaglia G, Busetti M, Gennaro R..
Fungicidal activity of five cathelicidin peptides against clinically isolated yeasts..
J Antimicrob Chemother, 58 (2006), pp. 950-959
Cabras T, Longhi R, Secundo F, Nocca G, Conti S, Polonelli L, Fanali C, Inzitari R, Petruzzelli R, Messana I, Castagnola M, Vitali A..
Structural and functional characterization of the porcine proline-rich antifungal peptide SP-B isolated from salivary gland granules..
J Pept Sci, 14 (2008), pp. 251-260
Carballeira NM, O'Neill R, Parang K..
Synthesis and antifungal properties of alpha-methoxy and alpha-hydroxyl substituted 4-thiatetradecanoic acids..
Chem Phys Lipids, 150 (2007), pp. 82-88
Cao Y, Dai B, Wang Y, Huang S, Xu Y, Gao P, Zhu Z, Jiang Y..
In vitro activity of baicalein against Candida albicans biofilms..
Int J Antimicrob Agents, 32 (2008), pp. 73-77
Casadevall A..
The third age of antimicrobial therapy..
Clin Infect Dis, 42 (2006), pp. 1414-1416
Cateau E, Rodier MH, Imbert C..
In vitro efficacies of caspofungin or micafungin catheter lock solutions on Candida albicans biofilm growth..
J Antimicrob Chemother, 62 (2008), pp. 153-155
Chamilos G, Lewis RE, Kontoyiannis DP..
Inhibition of Candida parapsilosis mitochondrial respiratory pathways enhances susceptibility to caspofungin..
Antimicrob Agents Chemother, 50 (2006), pp. 744-747
Chamilos G, Lewis RE, Kontoyiannis DP..
Lovastatin has significant activity against zygomycetes and interacts synergistically with voriconazole..
Antimicrob Agents Chemother, 50 (2006), pp. 96-103
Chayakulkeeree M, Rude TH, Toffaletti DL, Perfect JR..
Fatty acid synthesis is essential for survival of Cryptoccus neoformans and a potential fungicidal target..
Antimicrob Agents Chemother, 51 (2007), pp. 3537-3545
Chen L, Shen Z, Wu J..
Expression, purification and in vitro antifungal activity of acidic mammalian chitinase against Candida albicans, Aspergillus fumigatus and Trichophyton rubrum strains..
Clin Exp Dermatol, 34 (2009), pp. 55-60
Chiang LY, Ejzykowicz DE, Tian ZQ, Katz L, Filler SG..
Efficacy of ambruticin analogs in a murine model of invasive pulmonary aspergillosis..
Antimicrob Agents Chemother, 50 (2006), pp. 3464-3466
Clement M, Tremblay J, Lange M, Thibodeau J, Belhumeur P..
Whey-derived free fatty acids suppress the germination of Candida albicans in vitro..
FEMS Yeast Res, 7 (2007), pp. 276-285
Dalleau S, Cateau E, Berges T, Berjeaud JM, Imbert C..
In vitro activity of terpenes against Candida biofilms..
Int J Antimicrob Agents, 31 (2008), pp. 572-576
D'Auria FD, Tecca M, Strippoli V, Salvatore G, Battinelli L, Mazzanti G..
Antifungal activity of Lavandula angustifolia essential oil against Candida albicans yeast and mycelial form..
Med Mycol, 43 (2005), pp. 391-396
Dennis CG, Greco WR, Brun Y, Youn R, Slocum HK, Bernacki RJ, Lewis R, Wieder-hold N, Holland SM, Petraitiene R, Walsh TJ, Segal BH..
Effect of amphotericin B and micafungin combination on survival, histopathology, and fungal burden in experimental aspergillosis in the p47 mouse model of chronic granulomatous disease..
Antimicrob Agents Chemother, 50 (2006), pp. 422-427
Enoch DA, Ludlam HA, Brown NM..
Invasive fungal infections: a review of epidemiology and management options..
J Med Microbiol, 55 (2006), pp. 809-818
Espinel-Ingroff A..
Mechanisms of resistance to antifungal agents: yeasts and filamentous fungi..
Rev Iberoam Micol, 25 (2008), pp. 101-106
Fitzgerald-Hughes DH, Coleman DC, O'Connell BC..
Differentially expressed proteins in derivatives of Candida albicans displaying a stable histatin 3-resistant phenotype..
Antimicrob Agents Chemother, 51 (2007), pp. 2793-2800
Foldvari M, Jaafari MR, Radhi J, Segal D..
Efficacy of the antiadhesin octyl O-(2-acetamido-2-deoxy-β-D-galactopyranosyl)-(1-4)-2-O-propyl-β-D-galactopyranoside (fimbrigal-P) in a rat oral candidiasis model..
Antimicrob Agents Chemother, 49 (2008), pp. 2887-2894
Freifeld A, Arnold S, Ooi W, Chen F, Meyer T, Wheat LJ, Smedema M, Lemonte A, Connolly P..
Relationship of blood level and susceptibility in voriconazole treatment of histoplasmosis..
Antimicrob Agents Chemother, 51 (2007), pp. 2656-2657
Garcia-Effron G, Kontoyiannis DP, Lewis RE, Perlin DS..
Caspofungin-resistant Candida tropicalis strains causing breakthrough fungemia in patients at high risk for hematologic malignancies..
Antimicrob Agents Chemother, 52 (2005), pp. 4181-4183
Garcia-Effron G, Park S, Perlin DS..
Correlating echinocandin MIC and kinetic inhibition of fks1 mutant glucan synthases for Candida albicans: implications for interpretive breakpoints..
Antimicrob Agents Chemother, 53 (2009), pp. 112-122
Chitotriosidase and gene therapy for fungal infections. Cell Mol Life Sci. 2009. [In press]
Guinea J, Pelaez T, Recio S, Torres-Narbona M, Bouza E..
In vitro antifungal activities of isavuconazole (BAL-4815), voriconazole, and fluconazole against 1,007 isolates of zygomycete, Candida, Aspergillus, Fusarium, and Scedosporium species..
Antimicrob Agents Chemother, 52 (2008), pp. 1396-1400
Gumbo T, Drusano GL, Liu W, Kulawy RW, Fregeau C, Hsu V, Louie A..
Once-weekly micafungin therapy is as effective as daily therapy for disseminated candidiasis in mice with persistent neutropenia..
Antimicrob Agents Chemother, 51 (2007), pp. 968-974
Gumbo T, Hiemenz J, Ma L, Keirns JJ, Buell DN, Drusano GL..
Population pharmacokinetics of micafungin in adult patients..
Diagn Microbiol Infect Dis, 60 (2008), pp. 329-331
Hachem R, Bahna P, Hanna H, Stephens LC, Raad I..
EDTA as an adjunct antifungal agent for invasive pulmonary aspergillosis in a rodent model..
Antimicrob Agents Chemother, 50 (2006), pp. 1823-1827
Hasenoehrl A, Galic T, Ergovic G, Marsic N, Skerlev M, Mittendorf J, Geschke U, Schmidt A, Schoenfeld W..
In vitro activity and in vivo efficacy of icofungipen (PLD-118), a novel oral antifungal agent, against the pathogenic yeast Candida albicans..
Antimicrob Agents Chemother, 50 (2006), pp. 3011-3018
Henry CI, Mouya I, Latge JP..
Testing the efficacy of RNA interference constructs in Aspergillus fumigatus..
Curr Genet, 51 (2007), pp. 277-284
Hiemenz J, Cagnoni P, Simpson D, Devine S, Chao N, Keirns J, Lau W, Facklam D, Buell D..
Pharmacokinetic and maximum tolerated dose study of micafungin in combination with fluconazole versus fluconazole alone for prophylaxis of fungal infections in adult patients undergoing a bone marrow or peripheral stem cell transplant..
Antimicrob Agents Chemother, 49 (2005), pp. 1331-1336
Hodgetts S, Nooney L, Al-Akeel R, Curry A, Awad S, Matthews R, Burnie J..
Efungumab and caspofungin: pre-clinical data supporting synergy..
J Antimicrob Chemother, 61 (2008), pp. 1132-1139
Hope WW, Seibel NL, Schwartz CL, Arrieta A, Flynn P, Shad A, Albano E, Keirns JJ, Buell DN, Gumbo T, Drusano GL, Walsh TJ..
Population pharmacokinetics of mica-fungin in pediatric patients and implications for antifunghal dosing..
Antimicrob Agents Chemother, 51 (2007), pp. 3714-3719
Hope WW, Warn PA, Sharp A, Howard S, Kasai M, Louie A, Walsh TJ, Drusano GL, Denning DW..
Derivation of an in vitro drug exposure breakpoint for flucytosine against Candida albicans and the impact of the MIC growth rate, and resistance genotype on the antifungal effect..
Antimicrob Agents Chemother, 50 (2006), pp. 3680-3688
Jang WS, Li XS, Sun JN, Edgerton M..
The P-113 fragment of histatin 5 requires a specific peptide sequence for intracellular translocation in Candida albicans, which is independent of cell wall binding..
Antimicrob Agents Chemother, 52 (2008), pp. 497-504
Jiang B, Xu D, Allocco J, Parish C, Davison J, Veillette K, Sillaots S, Hu W, Rodriguez-Suarez R, Trosok S, Zhang L, Li Y, Rahkhoodaee F, Ransom T, Martel N, Wang H, Gauvin D, Wiltsie J, Wisniewski D, Salowe S, Kahn JN, Hsu MJ, Giacobbe R, Abruzzo G, Flattery A, Gill C, Youngman P, Wilson K, Bills G, Platas G, Pelaez F, Diez MT, Kauffman S, Becker J, Harris G, Liberator P, Roemer T..
PAP inhibitor with in vivo efficacy identified by Candida albicans genetic profiling of natural products..
Chem Biol, 15 (2008), pp. 363-374
Jung HJ, Sung WS, Yeo SH, Kim HS, Lee IS, Woo ER, Lee DG..
Antifungal effect of amentoflavone derived from Selaginella tamariscina..
Arch Pharm Res, 29 (2006), pp. 746-751
Kakeya H, Miyazaki Y, Senda H, Kobayashi T, Seki M, Izumikawa K, Yanagihara K, Yamamoto Y, Tashiro T, Kohno S..
Efficacy of SPK-843, a novel polyene antifungal, in comparison with amphotericin B, liposomal amphotericin B, and micafungin against murine pulmonary aspergillosis..
Antimicrob Agents Chemother, 52 (2008), pp. 1868-1870
Kanafani ZA, Perfect JR..
Resistance to antifungal agents: mechanisms and clinical impact..
Clin Infect Dis, 46 (2006), pp. 120-128
Kang TH, Hwang EI, Yun BS, Park KD, Kwon BM, Shin CS, Kim SU..
Inhibition of chitin synthases and antifungal activities by 2'-benzoyloxycinnamaldehyde from Pleuropterus cillinervis and its derivatives..
Biol Pharm Bull, 30 (2007), pp. 598-602
Kang TH, Hwang EI, Yun BS, Shin CS, Kim SU..
Chitin synthase 2 inhibitory activity of O-methyl pisiferic acid and 8,20-dihydroxy-9 (11), 13-abietadien-12-one, isolated from Chamaecyparis pisifera..
Biol Pharm Bull, 31 (2008), pp. 755-759
Keirns J, Sawamoto T, Holum M, Buell D, Wisemandle W, Alak A..
Steady-state pharmacokinetics of micafungin and voriconazole after separate and concomitant dosing in healthy adults..
Antimicrob Agents Chemother, 51 (2007), pp. 787-790
Kitamura A, Someya K, Hata M, Nakajima R, Takemura M..
Discovery of a small-molecule inhibitor of β-1,6-glucan synthesis..
Antimicrob Agents Chemother, 53 (2009), pp. 670-677
Krishnakumari V, Rangaraj N, Nagaraj R..
Antifungal activities of human beta-defensins HBD-1 to HBD-3 and their C-terminal analogs Phd1 to Phd3..
Antimicrob Agents Chemother, 53 (2009), pp. 256-260
Kunze B, Steinmetz H, Hofle G, Huss M, Wieczorek H, Reichenbach H..
Cruentaren, a new antifungal salicylate-type macrolide from Byssovorax cruenta (myxobacteria) with inhibitory effect on mitochondrial ATPase activity. Fermentation and biological properties..
J Antibiot (Tokyo), 59 (2006), pp. 664-668
Larsen RA, Pappas PG, Perfect J, Aberg JA, Casadevall A, Cloud GA, James R, Filler S, Dismukes WE..
Phase I evaluation of the safety and pharmacokinetics of murine-derived anticryptococcal antibody 18B7 in subjects with treated cryptococcal meningitis..
Antimicrob Agents Chemother, 49 (2005), pp. 952-958
Lass-Florl C, Griff K, Mayr A, Petzer A, Gastl G, Bonatti H, Freund M, Kropshofer G, Dierich MP, Nachbaur D..
Epidemiology and outcome of infections due to Aspergillus terreus: 10-year single centre experience..
Brit J Haematol, 131 (2005), pp. 201-207
Leung EH, Wong JH, Ng TB..
Concurrent purification of two defense proteins from French bean seeds: a defensin-like antifungal peptide and a hemagglutinin..
J Pept Sci, 14 (2008), pp. 349-353
Li XC, Jacob MR, Khan SI, Ashfaq MK, Babu KS, Agarwal AK, ElSohly HN, Manly SP, Clark AM..
Potent in vitro antifungal activities of naturally occurring acetylenic acids..
Antimicrob Agents Chemother, 52 (2008), pp. 2442-2448
Liu M, Healy MD, Dougherty BA, Esposito KM, Maurice TC, Mazzucco CE, Bruccoleri RE, Davison DB, Frosco M, Barrett JF, Wang YK..
Conserved fungal genes as potential targets for broad-spectrum antifungal drug discovery..
Eukaryot Cell, 5 (2006), pp. 638-649
Lupetti A, Brouwer CP, Bogaards SJ, Welling MM, De Heer E, Campa M, Van Dissel JT, Frissen RH, Nibbering PH..
Human lactoferrin-derived peptide's antifungal activities against disseminated Candida albicans infection..
J Infect Dis, 196 (2007), pp. 1416-1424
Maki K, Matsumoto S, Watabe E, Iguchi Y, Tomishima M, Ohki H, Yamada A, Ikeda F, Tawara S, Mutoh S..
Use of a serum-based antifungal susceptibility assay to predict the in vivo efficacy of novel echinocandin compounds..
Microbiol Immunol, 52 (2008), pp. 383-391
Martin de la Escalera C, Aller AI, Lopez-Oviedo E, Romero A, Martos AI, Canton E, Peman J, Garcia Martos P, Martin-Mazuelos E..
Activity of BAL 4815 against filamentous fungi..
Antimicrob Agents Chemother, 61 (2008), pp. 1083-1086
Martinez LR, Bryan RA, Apostolidis C, Morgenstern A, Casadevall A, Dadachova E..
Antibody-guided alpha radiation effectively damages fungal biofilms..
Antimicrob Agents Chemother, 50 (2006), pp. 2132-2136
Marx F, Binder U, Leiter E, Pocsi I..
The Penecillium chrysogenum antifungal protein PAF, a promising tool for the development of new antifungal therapies and fungal cell biology studies..
Cell Mol Life Sci, 65 (2008), pp. 445-454
Mattila PE, Metz AE, Rapaka RR, Bauer LD, Steele C..
Dectin-1 Fc targeting of Aspergillus fumigatus beta-glucans augments innate defense against invasive pulmonary aspergillosis..
Antimicrob Agents Chemother, 52 (2008), pp. 1171-1172
McCarron PA, Donnelly RF, Marouf W, Calvert DE..
Anti-adherent and antifungal activities of surfactant-coated poly (ethyleyanoacrylate) nanoparticles..
Int J Pharm, 340 (2007), pp. 182-190
Melcer A, Lacka I, Gabriel I, Wojciechowski M, Liberek B, Wisniewski A, Milewski S..
Rational design of N-alkyl derivatives of 2-amino-2-deoxy-d-glucitol-6P as antifungal agents..
Bioorg Med Chem Lett, 17 (2007), pp. 6602-6666
Messer SA, Diekema DJ, Boyken L, Tendolkar S, Hollis RJ, Pfaller MA..
Activities of micafungin against 315 invasive clinical isolates of fluconazole-resistant Candida spp..
J Clin Microbiol, 44 (2006), pp. 324-326
Meyer V..
A small protein that fights fungi: AFP as a new promising antifungal agent of biotechnological value..
Appl Microbiol Biotechnol, 78 (2008), pp. 17-28
Mitsuyama J, Nomura N, Hasimoto K, Yamada E, Nishikawa H, Kaeriyama M, Kimura A, Todo Y, Narita H..
In vitro and in vivo antifungal activities of T-2307, a novel arylamidine..
Antimicrob Agents Chemother, 52 (2008), pp. 1318-1324
Munoz A, Lopez-Garcia B, Marcos JF..
Studies on the mode of action of the anti-fungal hexapeptide PAF26..
Antimicrob Agents Chemother, 50 (2006), pp. 3847-3855
Nakamata K, Kurita T, Bhuiyan MS.A, Sato K, Noda Y, Yoda K..
KEGI/YFR042w encodes a novel Kre6-binding endoplasmic reticulum membrane protein responsible for β-1,6-glucan synthesis in Saccharomyces cerevisiae..
J Biol Chem, 282 (2007), pp. 34315-34324
Nazi I, Scott A, Sham A, Rossi L, Williamson PR, Kronstad JW, Wright GD..
Role of homoserine transacetylase as a new target for antifungal agents..
Antimicrob Agents Chemother, 51 (2007), pp. 1731-1736
Ng CK, Obando D, Widmer F, Wright LC, Sorrell TC, Jollife KA..
Correlation of anti-fungal activity with fungal phospholipase inhibition using a series of bisquater-nary ammonium salts..
J Med Chem, 49 (2006), pp. 811-816
Ngai PH, Ng TB..
A lectin with antifungal and mitogenic activities from red cluster pepper (Capsicum frutescens) seeds..
Appl Microbiol Biotechnol, 74 (2007), pp. 366-371
Okumura Y, Ogawa K, Uchiya K, Komori Y, Nonogaki T, Nikai T..
Biological properties of elastase inhibitor, AFLEI from Aspergillus flavus..
Nippon Ishinkin Gakkai Zasshi, 49 (2008), pp. 87-93
Omaetxebarria MJ, Moragues MD, Elguezabal N, Rodriguez-Alejandra A, Brena S, Schneider J, Polonelli L, Ponton J..
Antifungal and antitumor activities of a monoclonal antibody directed against a stress mannoprotein of Candida albicans..
Curr Mol Med, 5 (2005), pp. 393-401
Ota Y, Tatsuno K, Okugawa S, Yanagimoto S, Kitasawa T, Fukushima A, Tsukada K, Koike K..
Relationship between the initial dose of micafungin and its efficacy in patients with candidemia..
J Infect Chemother, 13 (2007), pp. 208-212
Pachl J, Svoboda P, Jacobs F, Vandewoude K, Van der Hoven B, Spronk P, Master-son G, Malbrain M, Aoun M, Garbino J, Takala J, Drgona L, Burnie J, Matthews R, for the Mycograb Invasive Candidiasis Study Group..
A randomized, blinded, multicenter trial of lipid-associated amphotericin B alone versus in combination with an antibody-based inhibitor of heat shock protein 90 in patients with invasive candidiasis..
Clin Infect Dis, 42 (2006), pp. 1404-1413
Paderu P, Garcia-Effron G, Balashov S, Delmas G, Park S, Perlin DS..
Serum differentially alters the antifungal properties of echinocandin drugs..
Antimicrob Agents Chemother, 51 (2007), pp. 2253-2256
Pai MP, Samples ML, Mercier RC, Spilde MN..
Activities and ultrastructural effects of antifungal combinations against simulated Candida endocardial vegetations..
Antimicrob Agents Chemother, 52 (2008), pp. 2367-2376
Pascual A, Calandra T, Bolay S, Buclin T, Bille J, Marchetti O..
Voriconazole therapeutic drug monitoring in patients with invasive mycoses improves efficacy and safety outcomes..
Clin Infect Dis, 46 (2008), pp. 201-211
Parish CA, Smith SK, Calati K, Zink D, Wilson K, Roemer T, Jiang B, Xu D, Bills G, Platas G, Peláez F, Díez MT, Tsou N, McKeown AE, Ball RG, Powles MA, Yeung L, Liberator P, Harris G..
Isolation and structure elucidation of parnafungins, antifungal natural products that inhibit mRNA polyadenylation..
J Am Chem Soc, 130 (2008), pp. 7060-7066
The in vitro activity of isavuconazole against Aspergillus species and zygomycetes according to EUCAST methodology. Antimicrob Agents Chemother. 2009. [In press].
Perlin DS..
Resistance to echinocandin-class antifungal drugs..
Drug Resist Updates, 10 (2007), pp. 121-130
Petraitiene R, Petraitis V, Kelaher AM, Sarafandi AA, Mickiene D, Groll AH, Sein T, Bacher J, Walsh TJ..
Efficacy, plasma pharmacokinetics, and safety of icofungipen, an inhibitor of Candida isoleucyl-tRNA synthetase, in treatment of experimental disseminated candidiasis in persistently neutropenic rabbits..
Antimicrob Agents Chemother, 49 (2005), pp. 2084-2092
Pfaller MA, Boyken L, Hollis RJ, Kroeger J, Messer SA, Tendolkar S, Diekema DJ..
In vitro susceptibility of invasive isolates of Candida spp. to anidulafungin, caspofungin, and micafungin: six years of global surveillance..
J Clin Microbiol, 46 (2008), pp. 150-156
Pfaller MA, Diekema DJ..
Epidemiology of invasive candidiasis: a persistent public health problem..
Clin Microbiol Rev, 20 (2007), pp. 133-163
Rauch I, Lundstrom L, Hell M, Sperl W, Kofler B..
Galanin message-associated peptide suppresses growth and the budded-to-hyphal-form transition of Candida albicans..
Antimicrob Agents Chemother, 51 (2007), pp. 4167-4170
Rodriguez-Suarez R, Xu D, Veillette K, Davison J, Sillaots S, Kauffman S, Hu W, Bowman J, Martel N, Trosok S, Wang H, Zhang L, Huang LY, Li Y, Rahkhoodaee F, Ransom T, Gauvin D, Douglas C, Youngman P, Becker J, Jiang B, Roemer T..
Mechanism-of-action determination of GMP synthase inhibitors and target validation in Candida albicans and Aspergillus fumigatus..
Chem Biol, 14 (2007), pp. 1163-1175
Rukayadi Y, Hwang JK..
In vitro antimycotic activity of xanthorrhizol isolated from Curcuma xanthorrhiza Roxb. against opportunistic filamentous fungi..
Phytother Res, 21 (2007), pp. 434-438
Saville SP, Lazzell AL, Bryant AP, Fretzen A, Monreal A, Solberg EO, Monteagudo C, Lopez-Ribot JL, Milne GT..
Inhibition of filamentation can be used to treat disseminated candidiasis..
Antimicrob Agents Chemother, 50 (2006), pp. 3312-3316
Segal BH, Walsh TJ..
Current approaches to diagnosis and treatment of invasive aspergillosis..
Am J Respir Crit Care Med, 173 (2006), pp. 707-717
Seifert H, Aurbach U, Stefanik D, Cornely O..
In vitro activities of isavuconazole and other antifungal agents against Candida bloodstream isolates..
Antimicrob Agents Chemother, 51 (2007), pp. 1818-1821
Serena C, Fernandez-Torres B, Pastor FJ, Trilles L, Dos Santos Lazera M, Nolard N, Guarro J..
In vitro interactions of micafungin with other antifungal drugs against clinical isolates of four species of Cryptococcus..
Antimicrob Agents Chemother, 49 (2005), pp. 2994-2996
Shubitz LF, Galgiani JN, Tian ZQ, Zhong Z, Timmermans P, Katz L..
Efficacy of ambruticin analogs in a murine model of coccidioidomycosis..
Antimicrob Agents Chemother, 50 (2006), pp. 3467-3469
Simon A, Kullberg BJ, Tripet B, Boerman OC, Zeeuwen P, Van der Ven-Jongekrijg J, Verweij P, Schalkwijk J, Hodges R, van der Meer JW.M, Netea MG..
Drosomycin-like defensin, a human homologue of Drosophila melanogaster drosomycin with antifungal activity..
Antimicrob Agents Chemother, 52 (2008), pp. 1407-1412
Smith J, Safdar N, Knasinski V, Simmons W, Bhavnani SM, Ambrose PG, Andes D..
Voriconazole therapeutic drug monitoring..
Antimicrob Agents Chemother, 50 (2006), pp. 1570-1572
Steinbach WJ, Cramer Jr RA, Perfect BZ, Henn C, Nielsen K, Heitman J, Perfect JR..
Calcineurin inhibition or mutation enhances cell wall inhibitors against Aspergillus fumigatus..
Antimicrob Agents Chemother, 51 (2007), pp. 2979-2981
In vitro activities of retigeric acid B alone and in combination with azole antifungal agents against Candida albicans. Antimicrob Agents Chemother. 2009. [In press]
Sung WS, Lee DG..
The candidacidal activity of indole-3-carbinol that binds with DNA..
IUBMB Life, 59 (2007), pp. 408-412
Sung WS, Lee J, Lee DG..
Fungicidal effect and the mode of action of piscidin 2 derived from hybrid striped bass..
Biochem Biophys Res Commun, 371 (2008), pp. 551-555
Tavares PM, Thevissen K, Cammue BP.A, Francois IEJ.A, Barreto-Bergter E, Taborda CP, Marques AF, Rodrigues ML, Nimrichter L..
In vitro activity of the antifungal plant defensin RsAFP2 against Candida isolates and its in vivo efficacy in prophylactic murine models of candidiasis..
Antimicrob Agents Chemother, 52 (2008), pp. 4522-4525
Thati B, Noble A, Rowan R, Creaven BS, Walsh M, McCann M, Egan D, Kavanagh K..
Mechanism of action of coumarin and silver(l)-coumarin complexes against the pathogenic yeast Candida albicans..
Toxicol In Vitro, 21 (2007), pp. 801-808
Tomishima M, Ohki H, Yamada A, Maki K, Ikeda F..
Novel echinocandin antifungals. Part 2: optimization of the side chain of the natural product FR901379. Discovery of micafungin..
Bioorg Med Chem Lett, 18 (2008), pp. 2886-2890
Vallon-Eberhard A, Makovitzki A, Beauvais A, Latge JP, Jung S, Shai Y..
Efficient clearance of Aspergillus fumigatus in murine lungs by an ultrashort antimicrobial lipopeptide, palmitoyl-lys-ala-Dala-lys..
Antimicrob Agents Chemother, 52 (2008), pp. 3118-3126
Viera DB, Carmona-Ribeiro RM..
Cationic lipids and surfactants as antifungal agents: mode of action..
J Antimicrob Chemother, 58 (2006), pp. 760-767
Wakiec W, Gabriel I, Prasad R, Becker JM, Payne JW, Milewski S..
Enhanced susceptibility to antifungal oligopeptides in yeast strains overexpressing ABC multi-drug efflux pumps..
Antimicrob Agents Chemother, (2008), pp. 4057-4063
Widmer F, Wright LC, Obando D, Handke R, Ganendren R, Ellis DH, Sorrell TC..
Hexadecylphosphocholine (miltefosine) has broad-spectrum fungicidal activity and is efficacious in a mouse model of cryptococcosis..
Antimicrob Agents Che-mother, 50 (2006), pp. 414-421
Xu D, Jiang B, Ketela T, Lemieux S, Veillette K, Martel N, Davison J, Sillaots S, Trosok S, Bachewich C, Bussey H, Youngman P, Roemer T..
Genome-wide fitness test and mechanism-of-action studies of inhibitory compounds in Candida albi-cans..
Yano T, Aoyagi A, Kozuma S, Kawamura Y, Tanaka I, Suzuki Y, Takamatsu Y, Takatsu T, Inukai M..
Pleofungins, novel inositol phosphorylceramide synthase inhibitors, from Phoma sp. SANK 13899. Taxonomy, fermentation, isolation, and biological activities..
J Antibiot (Tokyo), 60 (2007), pp. 136-142
Yim NH, Hwang EI, Yun BS, Park KD, Moon JS, Lee SH, Sung ND, Kim SU..
Sesquiterpene furan compound C-J-01, a novel chitin synthase 2 inhibitor from Chloran-thus japonicus SIEB..
Biol Pharm Bull, 31 (2008), pp. 1041-1044
Yordanov M, Dimitrova P, Patkar S, Saso L, Ivanovska N..
Inhibition of Candida albicans extracellular enzyme activity by selected natural substances and their application in Candida infection..
Can J Microbiol, 54 (2008), pp. 435-440
Yu F, Zaleta-Rivera K, Zhu X, Huffman J, Millet JC, Harris SD, Yuen G, Li XC, Du L..
Structure and biosynthesis of heat-stable antifungal factor (HSAF), a broad-spectrum antimycotic with a novel mode of action..
Antimicrob Agents Chemother, 51 (2007), pp. 64-72
Zaas AK..
In the modern day, what are the potential advantages of echinocandins over azoles and polyenes in drug interactions? J Invasive Fungal Infect, 1 (2007), pp. 133-142
Zhu J, Luther PW, Leng Q, Mixson AJ..
Synthetic histidine-rich peptides inhibit Candida species and other fungi in vitro: role of endocytosis and treatment implications..
Antimicrob Agents Chemother, 50 (2006), pp. 2797-2805
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