Silibinin triggers yeast apoptosis related to mitochondrial Ca2+ influx in Candida albicans

Candida albicans is a common yeast that resides in the human body, but can occasionally cause systemic fungal infection, namely candidiasis. As this infection rate is gradually increasing, it is becoming a major problem to public health. Accordingly, we for the first time investigated the antifungal activity and mode of action of silibinin, a natural product extracted from Silybum marianum (milk thistle), against C. albicans. On treatment with 100 μM silibinin, generation of reactive oxygen species (ROS) from mitochondria, which can cause yeast apoptosis via oxidative stress, was increased by 24.17% compared to that in untreated cells. Subsequently, we found disturbances in ion homeostasis such as release of intracellular K⁺ and accumulation of cytoplasmic and mitochondrial Ca²⁺. Among these phenomena, mitochondrial Ca²⁺ overload particularly plays a crucial role in the process of apoptosis, promoting the activation of pro-apoptotic factors. Therefore, we investigated the significance of mitochondrial Ca²⁺ in apoptosis by employing 20 mM ruthenium red (RR). Additional apoptosis hallmarks such as mitochondrial membrane depolarization, cytochrome c release, caspase activation, phosphatidylserine (PS) exposure, and DNA damage were observed in response to silibinin treatment, whereas RR pre-treatment seemed to block these responses. In summary, our results suggest that silibinin induces yeast apoptosis mediated by mitochondrial Ca²⁺ signaling in C. albicans.     

Nerol triggers mitochondrial dysfunction and disruption via elevation of Ca2+ and ROS in Candida albicans

The antifungal activity of Nerol (NEL) against Candida albicans, a pathogenic fungus, has a minimum inhibitory concentration (MIC) of 4.4 mM that causes noteworthy candidacidal activity through an apoptosis-like mechanism. Calcium (Ca²⁺) levels and reactive oxygen species (ROS) production, which are the major causes of apoptosis, were determined in C. albicans cells treated with NEL and were found to increase, which related to mitochondrial dysfunction and disruption. A series of characteristic changes of apoptosis caused by NEL, including mitochondrial membrane depolarization, cytochrome c (cyt c) release, and metacaspase activation were examined using a flow cytometer and Western blot. The results showed that an increase in intracellular Ca²⁺ and ROS led to dramatically decreased mitochondrial membrane potential (MMP); cyt c was also released from the mitochondria to the cytosol. Other early apoptotic features were also observed with the metacaspase activation. Finally, the morphological changes of the cells were observed, including phosphatidylserine (PS) externalization, nuclear condensation, and DNA fragmentation through Annexin V-FITC and PI double staining, TUNEL assay, and DAPI staining. The results supported the hypothesis that NEL was involved in the apoptosis of C. albicans cells not only at the early stages, but also at the late stages. In summary, NEL can trigger mitochondrial dysfunction and disruption via elevation of Ca²⁺ and ROS leading to apoptosis in C. albicans. This research on the mechanism of cell death triggered by NEL against C. albicans has important significance for providing a novel treatment of C. albicans infections.     

Role of calcium in reactive oxygen species-induced apoptosis in Candida albicans: an antifungal mechanism of antimicrobial peptide,PMAP-23

PMAP-23 (RIIDLLWRVRRPQKPKFVTVWVR-NH₂) is an antimicrobial peptide (AMP) derived from porcine myeloid. Membrane disruption is thought to underpin the anticandidal activity of PMAP-23. However, many AMPs act via mechanisms other than simple membrane permeabilisation. Here, we investigated the anticandidal mechanism of PMAP-23 at low concentrations. Membrane disruption and depolarisation and rapid K⁺ efflux were observed in Candida albicans cells treated with 5?µM PMAP-23. In contrast, 2.5?µM PMAP-23 caused membrane depolarisation and K⁺ efflux without membrane disruption. The lower PMAP-23 concentration increased cytosolic and mitochondrial Ca²⁺ levels. Disruption of Ca²⁺ homeostasis altered the NAD⁺/NADH ratio and resulted in reactive oxygen species (ROS) accumulation and glutathione oxidation. PMAP-23 treatment also stimulated apoptosis, as evidenced by metacaspase activation, DNA fragmentation, and phosphatidylserine externalisation. Pretreatment with the mitochondrial Ca²⁺ uptake inhibitor (ruthenium red) or ROS scavenger (N-acetylcysteine) attenuated these apoptotic events. Our results suggest that PMAP-23 induces apoptosis as antifungal mechanism, and mitochondrial Ca²⁺-induced ROS is major factor to trigger the apoptosis. Thus, the anticandidal activity of PMAP-23 is not based solely on disruption of biological membranes but also involves induction of apoptosis via mitochondrial Ca²⁺-dependent ROS. PMAP-23 mode of action sheds new light on the antifungal mechanism of antimicrobial peptides, supporting the role of Ca²⁺ and ROS in apoptosis regulation.     

β-amyrin-induced apoptosis in Candida albicans triggered by calcium

The emergence of drug-resistant pathogens has urged researchers to discover alternatives for traditional antibiotics. β-amyrin, which is included in the category of triterpenoids extracted from plants, is known for its antimicrobial activity, although the underlying mechanism has not yet been revealed. This study was conducted to elucidate the antifungal mode of action of β-amyrin against Candida albicans. Based on the relevance between triterpenoids and oxidative molecules, reactive oxygen species (ROS) concentrations were detected, which showed a noticeable increment. Disruption of Ca²⁺ homeostasis in the cytosol was additionally analyzed, which was supported by interactions between two. Subsequently, decrease in mitochondrial membrane potential, increment of mitochondrial Ca²⁺, and ROS concentration were monitored, which suggested mitochondrial dysfunction modulated by Ca²⁺. Further investigation confirmed oxidative damage through glutathione reduction and DNA fragmentation. Accumulation of lethal damages resulted in the activation of caspases and externalization of phosphatidylserine, indicating the induction of yeast apoptosis by β-amyrin in C. albicans.     

Membrane damage as first and DNA as the secondary target for anti‐candidal activity of antimicrobial peptide P7 derived from cell‐penetrating peptide ppTG20 against Candida albicans

P7, a peptide analogue derived from cell‐penetrating peptide ppTG20, possesses antibacterial and antitumor activities without significant hemolytic activity. In this study, we investigated the antifungal effect of P7 and its anti‐Candida acting mode in Candida albicans. P7 displayed antifungal activity against the reference C. albicans (MIC = 4 μM), Aspergilla niger (MIC = 32 μM), Aspergillus flavus (MIC = 8 μM), and Trichopyton rubrum (MIC = 16 μM). The effect of P7 on the C. albicans cell membrane was examined by investigating the calcein leakage from fungal membrane models made of egg yolk l ‐phosphatidylcholine/ergosterol (10 : 1, w/w) liposomes. P7 showed potent leakage effects against fungal liposomes similar to Melittin‐treated cells. C. albicans protoplast regeneration assay demonstrated that P7 interacted with the C. albicans plasma membrane. Flow cytometry of the plasma membrane potential and integrity of C. albicans showed that P7 caused 60.9 ± 1.8% depolarization of the membrane potential of intact C. albicans cells and caused 58.1 ± 3.2% C. albicans cell membrane damage. Confocal laser scanning microscopy demonstrated that part of FITC‐P7 accumulated in the cytoplasm. DNA retardation analysis was also performed, which showed that P7 interacted with C. albicans genomic DNA after penetrating the cell membrane, completely inhibiting the migration of genomic DNA above the weight ratio (peptide : DNA) of 6. Our results indicated that the plasma membrane was the primary target, and DNA was the secondary intracellular target of the mode of action of P7 against C. albicans. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.     

Inhibitory effect of extracts from Brazilian medicinal plants on the adhesion of <Emphasis Type="Italic">Candida albicans</Emphasis> to buccal epithelial cells

Plants are known to produce a plethora of secondary metabolites which are recognized as a useful source of new drugs or drug leads. Extracts and fractions of Schinus terebinthifolius Raddi (Anacardiaceae), Piper regnellii C.D.C. (Piperaceae), Rumex acetosa L. (Polygonaceae), and Punica granatum L. (Punicaceae) were assessed for their antifungal activity against eight clinical isolates of C. albicans. They were also evaluated for their effect on the adhesion of these C. albicans isolates to buccal epithelial cells (BECs). The ethyl acetate fraction from the leaves of S. terebinthifolius showed promising activity, inhibiting the growth of three C. albicans isolates at 7.8 μg ml⁻¹ and significantly inhibiting their adhesion to BEC at 15 μg ml⁻¹ . In addition, this fraction did not show cytotoxic activity against murine macrophages. The results show the potential of the plant extracts studied as a source of new antifungal compounds. Further studies are necessary for isolation and characterization of the active compounds of these plants.     

Anti-Candida property of a lignan glycoside derived from Styrax japonica S. et Z. via membrane-active mechanisms

Styraxjaponoside C was investigated with respect to its antifungal activity and mechanisms of action. Devoid of hemolytic activity, Styraxjaponoside C demonstrated an antifungal effect against the human pathogenic yeast Candida albicans in an energy-independent manner. To characterize the mechanisms of the antifungal activity of Styraxjaponoside C, fluorescence analysis with membrane probe 1,6-diphenyl-1,3,5-hexatriene, and flow cytometric analysis on C. albicans were conducted. The results showed that Styraxjaponosdie C induced cytoplasmic membrane perturbation. The current study suggested that Styraxjaponoside C was active against C. albicans with membrane-active mechanisms.     

Roles of Cch1 and Mid1 in Morphogenesis, Oxidative Stress Response and Virulence in Candida albicans

Ca²⁺ channel Cch1, and its subunit Mid1, has been suggested as the protein complex responsible for mediating Ca²⁺ influx, which is often employed by fungal cells to maintain cell survival. The abilities of morphological switch and response to stress conditions are closely related to pathogenicity in Candida albicans. Cch1 and Mid1 activity are required for virulence of Cryptococcus neoformans and Claviceps purpurea, respectively. To investigate whether Cch1 and Mid1 also play a role in the virulence of C. albicans, we constructed cch1Δ/Δ and mid1Δ/Δ mutant strains for functional analysis of CCH1 and MID1. Although both of the mutants displayed the ability of yeast-to-hypha transition, they were defective in hyphae maintenance and invasive growth. Interestingly, deletion of CCH1 or MID1 in C. albicans led to an obvious defect phenotype in oxidative stress response. Moreover, the virulence of the mutants was reduced in a mouse model. Our results demonstrated that Cch1 and Mid1 activity are related to the virulence of C. albicans and may provide a new antifungal target.     

Antifungal Activity of Magnesium Oxide Nanoparticles: Effect on the Growth and Key Virulence Factors of Candida albicans

The aim of this research was to study the effects of different concentrations of magnesium oxide nanoparticles (MgO NPs) on the growth and key virulence factors of Candida albicans (C. albicans). The minimum inhibitory concentration (MIC) of MgO NPs against C. albicans was determined by the micro-broth dilution method. A time-kill curve of MgO NPs and C. albicans was established to investigate the ageing effect of MgO NPs on C. albicans. Crystal violet staining, the MTT assay, and inverted fluorescence microscopy were employed to determine the effects of MgO NPs on C. albicans adhesion, two-phase morphological transformation, biofilm biomass, and metabolic activity. The time-kill curve showed that MgO NPs had fungicidal and antifungal activity against C. albicans in a time- and concentration-dependent manner. Semi-quantitative crystal violet staining and MTT assays showed that MgO NPs significantly inhibited C. albicans biofilm formation and metabolic activity, and the difference was statistically significant (p?<?0.001). Inverted fluorescence microscopy showed that MgO NPs could inhibit the formation of C. albicans biofilm hyphae. Adhesion experiments showed that MgO NPs significantly inhibited the initial adhesion of C. albicans (p?<?0.001). This study demonstrates that MgO NPs can effectively inhibit the growth, initial adhesion, two-phase morphological transformation, and biofilm formation of C. albicans and is an antifungal candidate.

     

Antibiofilm Activity of Invasive Plants against Candida albicans: Focus on Baccharis halimifolia Essential Oil and Its Compounds

The extracts of five invasive plants were investigated for antifungal and antibiofilm activities against Candida albicans, C. glabrata, C. krusei, and C. parapsilosis. The antifungal activity was evaluated using the microdilution assay and the antibiofilm effect by measurement of the metabolic activity. Ethanol and ethanol-water extracts of Reynoutria japonica leaves inhibited 50 % of planktonic cells at 250 μg mL⁻¹ and 15.6 μg mL⁻¹, respectively. Ethanol and ethanol-water extracts of Baccharis halimifolia inhibited >75 % of the mature biofilm of C. albicans at 500 μg mL⁻¹. The essential oil (EO) of B. halimifolia leaves was the most active (50 % inhibition (IC₅₀) at 4 and 74 μg mL⁻¹against the maturation phase and 24 h old-biofilms of C. albicans, respectively). Oxygenated sesquiterpenes were the primary contents in this EO (62.02 %), with β-caryophyllene oxide as the major component (37 %). Aromadendrene oxide-(2), β-caryophyllene oxide, and (±)-β-pinene displayed significant activities against the maturation phase (IC₅₀=9–310 μ mol l⁻¹) and preformed 24 h-biofilm (IC₅₀=38–630 μ mol l⁻¹) of C. albicans with very low cytotoxicity for the first two compounds. C. albicans remained the most susceptible species to this EO and its components. This study highlighted for the first time the antibiofilm potential of B. halimifolia, its EO and some of its components.     

The antimicrobial peptide, psacotheasin induces reactive oxygen species and triggers apoptosis in Candida albicans

Previously, the antimicrobial effects and membrane-active action of psacotheasin in Candida albicans were investigated. In this study, we have further found that a series of characteristic cellular changes of apoptosis in C. albicans can be induced by the accumulation of intracellular reactive oxygen species, specifically hydroxyl radicals, the well-known important regulators of apoptosis. Cells treated with psacotheasin showed diagnostic markers in yeast apoptosis at early stages: phosphatidylserine externalization from the inner to the outer membrane surface, visualized by Annexin V-staining; mitochondrial membrane depolarization, observed by DiOC₆(3) staining; and increase of metacaspase activity, measured using the CaspACE FITC-VAD-FMK. Moreover, DNA fragmentation and condensation also revealed apoptotic phenomena at late stages through the TUNEL assay staining and DAPI staining, respectively. Taken together, our findings suggest that psacotheasin possess an antifungal property in C. albicans via apoptosis as another mode of action.     

Reactive oxygen species modulate itraconazole-induced apoptosis via mitochondrial disruption in Candida albicans

Itraconazole (ITC), a well-known fungistatic agent, has potent fungicidal activity against Candida albicans. However, its mechanism of fungicidal activity has not been elucidated yet, and we aimed to identify the mechanism of ITC against C. albicans. ITC caused cell shrinkage via potassium leakage through the ion channel. Since shrunken cells could indicate apoptosis, we investigated apoptotic features. Annexin V-FITC and TUNEL assays indicated that fungicidal activity of ITC was involved in apoptosis. Subsequently, we confirmed an intracellular factor that could cause apoptosis. ITC treatment caused reactive oxygen species (ROS) accumulation. To confirm whether ROS is related with ITC-triggered cell death, cell viability was examined using the ROS scavenger N-acetylcysteine (NAC). NAC pretreatment recovered ITC-induced cell death, indicating that antifungal activity of ITC is associated with ROS, which is also confirmed by impaired glutathione-related antioxidant system and oxidized intracellular lipids. Moreover, ITC-induced mitochondrial dysfunction, in turn, triggered cytochrome c release and metacaspase activation, leading to apoptosis. Unlike the only ITC-treatment group, cells with NAC pretreatment did not show significant damage to mitochondria, and attenuated apoptotic features. Therefore, our results suggest that ITC induces apoptosis as fungicidal mechanism, and intracellular ROS is major factor to trigger the apoptosis by ITC in C. albicans.     

The plant defensin RsAFP2 induces cell wall stress, septin mislocalization and accumulation of ceramides in Candida albicans

The antifungal plant defensin RsAFP2 isolated from radish interacts with fungal glucosylceramides and induces apoptosis in Candida albicans. To further unravel the mechanism of RsAFP2 antifungal action and tolerance mechanisms, we screened a library of 2868 heterozygous C. albicans deletion mutants and identified 30 RsAFP2‐hypersensitive mutants. The most prominent group of RsAFP2 tolerance genes was involved in cell wall integrity and hyphal growth/septin ring formation. Consistent with these genetic data, we demonstrated that RsAFP2 interacts with the cell wall of C. albicans, which also contains glucosylceramides, and activates the cell wall integrity pathway. Moreover, we found that RsAFP2 induces mislocalization of septins and blocks the yeast‐to‐hypha transition in C. albicans. Increased ceramide levels have previously been shown to result in apoptosis and septin mislocalization. Therefore, ceramide levels in C. albicans membranes were analysed following RsAFP2 treatment and, as expected, increased accumulation of phytoC24‐ceramides in membranes of RsAFP2‐treated C. albicans cells was detected. This is the first report on the interaction of a plant defensin with glucosylceramides in the fungal cell wall, causing cell wall stress, and on the effects of a defensin on septin localization and ceramide accumulation.     

Baicalin prevents Candida albicans infections via increasing its apoptosis rate

Background

These experiments were employed to explore the mechanisms underlying baicalin action on Candida albicans.

Methodology and principal findings

We detected the baicalin inhibition effects on three isotope-labeled precursors of ³H-UdR, ³H-TdR and ³H-leucine incorporation into C. albicans using the isotope incorporation technology. The activities of Succinate Dehydrogenase (SDH), cytochrome oxidase (CCO) and Ca²⁺–Mg²⁺ ATPase, cytosolic Ca²⁺ concentration, the cell cycle and apoptosis, as well as the ultrastructure of C.albicans were also tested. We found that baicalin inhibited ³H-UdR, ³H-TdR and ³H-leucine incorporation into C.albicans (P < 0.005). The activities of the SDH and Ca²⁺–Mg²⁺ ATPase of C.albicans in baicalin groups were lower than those in control group (P < 0.05). Ca²⁺ concentrations of C. albicans in baicalin groups were much higher than those in control group (P < 0.05). The ratio of C.albicans at the G0/G1 stage increased in baicalin groups in dose dependent manner (P < 0.01). There were a significant differences in the apoptosis rate of C.albicans between baicalin and control groups (P < 0.01). After 12–48 h incubation with baicalin (1 mg/ml), C. albicans shown to be markedly damaged under transmission electron micrographs.

Innovation and significance

Baicalin can increase the apoptosis rate of C. albicans. These effects of Baicalin may involved in its inhibiting the activities of the SDH and Ca²⁺–Mg²⁺ ATPase, increasing cytosolic Ca²⁺ content and damaging the ultrastructure of C. albicans.     

Biochemical characterization of Ca2+/calmodulin dependent protein kinase from Candida albicans

A multifunctional Ca²⁺/calmodulin dependent protein kinase was purified approximately 650 fold from cytosolic extract of Candida albicans. The purified preparation gave a single band of 69 kDa on sodium dodecyl sulfate polyacrylamide gel electrophoresis with its native molecular mass of 71 kDa suggesting that the enzyme is monomeric. Its activity was dependent on calcium, calmodulin and ATP when measured at saturating histone IIs concentration. The purified Ca²⁺/CaMPK was found to be autophosphorylated at serine residue(s) in the presence of Ca²⁺/calmodulin and enzyme stimulation was strongly inhibited by W-7 (CaM antagonist) and KN-62 (Ca²⁺/CaM dependent PK inhibitor). These results confirm that the purified enzyme is Ca²⁺/CaM dependent protein kinase of Candida albicans. The enzyme phosphorylated a number of exogenous and endogenous substrates in a Ca²⁺/calmodulin dependent manner suggesting that the enzyme is a multifunctional Ca²⁺/calmodulin-dependent protein kinase of Candida albicans.     

Mechanism of action of novel synthetic dodecapeptides against Candida albicans

Background

Three de novo designed low molecular weight cationic peptides (IJ2, IJ3 and IJ4) containing an unnatural amino acid α,β-didehydrophenylalanine (?Phe) exhibited potent antifungal activity against fluconazole (FLC) sensitive and resistant clinical isolates of Candida albicans as well as non-albicans and other yeast and filamentous pathogenic fungi. In the present study, their synthesis, susceptibility of different fungi and the mechanism of anti-candidal action have been elucidated.

Methods

The antimicrobial peptides (AMPs) were synthesized by solid-phase method and checked for antifungal activity against different yeasts and fungi by broth microdilution method. Anti-candidal mode of action of the peptides was investigated through detecting membrane permeabilization by confocal microscopy, Reactive Oxygen Species (ROS) generation by fluorometry, apoptosis and necrosis by flow cytometry and cell wall damage using Scanning and Transmission Electron Microscopy.

Results and conclusions

The MIC of the peptides against C. albicans and other yeast and filamentous fungal pathogens ranged between 3.91 and 250 μM. All three peptides exhibited effect on multiple targets in C. albicans including disruption of cell wall structures, compromised cell membrane permeability leading to their enhanced entry into the cells, accumulation of ROS and induction of apoptosis. The peptides also showed synergistic effect when used in combination with fluconazole (FLC) and caspofungin (CAS) against C. albicans.

General significance

The study suggests that the AMPs alone or in combination with conventional antifungals hold promise for the control of fungal pathogens, and need to be further explored for treatment of fungal infections.     

ClTI,a Kunitz trypsin inhibitor purified from Cassia leiandra Benth. seeds,exerts a candidicidal effect on Candida albicans by inducing oxidative stress and necrosis

Cassia leiandra is an Amazonian plant species that is used popularly for the treatment of mycoses. Recently, a protease inhibitor, named ClTI, with insecticidal activity against Aedes aegypti, was purified from the mature seeds of C. leiandra. In this work, we show that ClTI has antifungal activity against Candida species and describe its mode of action towards Candida albicans. This study is relevant because the nosocomial infections caused by Candida species are a global public health problem that, together with the growing resistance to current drugs, has increased the urgency of the search for new antifungal compounds. ClTI inhibited the growth of Candida albicans, Candida tropicalis, Candida parapsilosis, and Candida krusei. However, ClTI was more potent against C. albicans. The candidicidal mode of action of ClTI on C. albicans involves enhanced cell permeabilization, alteration of the plasma membrane proton-pumping ATPase function (H+ -ATPase), induction of oxidative stress, and DNA damage. ClTI also exhibited antibiofilm activity and non-cytotoxicity to mammalian cells. These results indicate that ClTI is a promising candidate for the future development of a new, natural, and safe agent for the treatment of infections caused by C. albicans.     

Antifungal activity of hypocrellin compounds and their synergistic effects with antimicrobial agents against Candida albicans

Candida albicans is a common human fungal pathogen. The previous study revealed that quinone compounds showed antimicrobial activity against C. albicans by inhibiting cell growth. However, it was unclear whether quinones have other antifungal effects against C. albicans in addition to fungicidal effects. In this study, we assessed the inhibitory activity of a total of 25 quinone compounds against C. albicans morphological transition, which is essential for the pathogenicity of C. albicans. Several quinones exhibited strong inhibition of mycelium formation by C. albicans SC5314. Three leading compounds, namely hypocrellins A, B and C, also exhibited marked attenuation of C. albicans SC5314 virulence in both human cell lines and mouse infection models. These three compounds significantly suppressed the proliferation of C. albicans SC5314 cells in a mouse mucosal infection model. Intriguingly, hypocrellins not only attenuated the cytotoxicity of a nystatin-resistant C. albicans strain but also showed excellent synergistic effects with antifungal agents against both wild-type C. albicans SC5314 and the drug-resistant mutant strains. In addition, hypocrellins A, B and C interfered with the biological functions and virulence of various clinical Candida species, suggesting the promising potential of these compounds for development as new therapeutic agents against infections caused by Candida pathogens.     

Existence of Hyphal Extension Factor and Hyphal Extension Inhibitor in the Hyphae of Rhizoctonia solani

Brefeldin A (BFA) is an antibiotic having diverse biological effects such as antifungal, antiviral and antitumor activities. The effect of BFA on biosynthesis of cellular components was examined to elucidate the mode of action of BFA using C. albicans IAM 4888.

When C. albicans was grown in the presence of BFA, cells became rounded and enlarged several times larger than the untreated control cells. Cell walls of the treated cells became irregular and a number of Sudan III-stainable lipid droplets was formed in the cytoplasm. Accompanying these morphological changes, a marked alteration occurred in the cellular lipid composition; neutral lipids increased whereas phospholipid decreased. [¹⁴C]Acetate incorporation into the lipid fraction proceeded in accordance with the growth in the presence of BFA. On the other hand, [³²P]orthophosphate incorporation into phospholipid was severely inhibited. Incorporation of radiolabeled precursors into DNA, RNA and protein was not affected on a cell weight basis.     

Glutamine analogues containing a keto function – novel inhibitors of fungal glucosamine-6-phosphate synthase

A series of novel inhibitors of glucosamine-6-phosphate synthase, analogues of AADP and BADP, have been synthesized and their inhibitory, lipophilic and antifungal properties have been tested. The improvement in lipophilicity has not much affected the antifungal activity of the new compounds. Dipeptides containing norvaline and selected inhibitors have shown substantial activity against S. cerevisiae and C. glabrata and only poor activity against C. albicans strain. These peptides do not seem to be toxic towards human cells.