Synthesis and Antifungal Properties of Compounds which Target the α‐Aminoadipate Pathway.

Palmer, David R. J.; Balogh, H.; Ma, Guofang; Zhou, Xing; Marko, Martha; Kaminskyj, Susan G. W.

doi:10.1002/chin.200419080

Cited by 13 publications

(20 citation statements)

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“…A. nidulans grows well in medium containing ≥1% ethanol as a sole carbon source (Fernández-Ábalos et al 1998;Palmer et al 2004), and it tolerates 1% DMSO without noticeable morphological effects. Average MT index and growth rate for populations of untreated, 0.1% ethanol-treated, and 0.25% DMSO-treated A. nidulans hyphae are shown in Fig.…”

Section: Cytoplasmic Microtubules In Aspergillus Nidulans Hyphaementioning

confidence: 99%

Growth rate of Aspergillus nidulans hyphae is independent of a prominent array of microtubules

Hubbard

Kaminskyj

2007

Mycol Progress

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Roles for the microtubule (MT) cytoskeleton in fungal growth include mitosis and nuclear migration but otherwise are less clearly understood. Confocal microscopy was used to quantify MT abundance and growth rate in hyphae of a haploid Aspergillus nidulans strain containing green fluorescent protein (GFP)-α-tubulin. There was no correlation between growth rate and MT abundance for 112 growing hyphae in an untreated population. However, 109 nongrowing hyphae from the same group had lower average MT abundance. Results for untreated cells were compared with cells treated for 30-120 min with the MT drugs benomyl and taxol, the actin drug latrunculin B, and with solvents used for the drug treatments. Compared with their respective controls, MT abundance was significantly increased by dimethyl sulfoxide (DMSO), significantly reduced by benomyl, and moderately increased by latrunculin, but was unaffected by ethanol. In the same cells, growth rates were significantly increased by ethanol and taxol, significantly reduced by latrunculin, and unaffected by DMSO. Average hyphal growth rate in the first 60 min following 1 μg/ml benomyl treatment was statistically similar to untreated cells, despite the absence of visible MTs after 2 min of treatment. However, growth rate was significantly reduced by 2.5 μg/ml benomyl over the same time period, implying additional effects at the higher concentration. For individual hyphae in each treatment, growth rates varied over short time periods; treatment with 0.1% ethanol substantially increased this variability. Growth rates of taxol-treated hyphae decreased following fluorescence observation, suggesting a possible application to cancer chemotherapy. Overall, there was no correlation between cytoplasmic MT abundance and A. nidulans growth rate within 2 h of cytoskeletal drug or solvent treatment.Abbreviations DIC differential interference contrast GFP green fluorescent protein MT microtubule TEM transmission electron microscopy

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Section: Cytoplasmic Microtubules In Aspergillus Nidulans Hyphaementioning

confidence: 99%

Growth rate of Aspergillus nidulans hyphae is independent of a prominent array of microtubules

Hubbard

Kaminskyj

2007

Mycol Progress

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“…Similarly, the AA pathway in fungi has been proposed as a valuable target for antifungal therapy. Indeed, several researchers have developed antifungal agents that specifically inhibit the AA pathway in pathogenic fungi [5,6,7]. …”

Section: Introductionmentioning

confidence: 99%

The lysine biosynthetic enzyme Lys4 influences iron metabolism, mitochondrial function and virulence in Cryptococcus neoformans

Park

et al. 2016

Biochemical and Biophysical Research Communications

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The lysine biosynthesis pathway via α-aminoadipate in fungi is considered an attractive target for antifungal drugs due to its absence in mammalian hosts. The iron-sulfur cluster-containing enzyme homoaconitase converts homocitrate to homoisocitrate in the lysine biosynthetic pathway, and is encoded by LYS4 in the model yeast Saccharomyces cerevisiae. In this study, we identified the ortholog of LYS4 in the human fungal pathogen, Cryptococcus neoformans, and found that LYS4 expression is regulated by iron levels and by the iron-related transcription factors Hap3 and HapX. Deletion of the LYS4 gene resulted in lysine auxotrophy suggesting that Lys4 is essential for lysine biosynthesis. Our study also revealed that lysine uptake was mediated by two amino acid permeases, Aap2 and Aap3, and influenced by nitrogen catabolite repression (NCR). Furthermore, the lys4 mutant showed increased sensitivity to oxidative stress, agents that challenge cell wall/membrane integrity, and azole antifungal drugs. We showed that these phenotypes were due in part to impaired mitochondrial function as a result of LYS4 deletion, which we propose disrupts iron homeostasis in the organelle. The combination of defects are consistent with our observation that the lys4 mutant was attenuated virulence in a mouse inhalation model of cryptococcosis.

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“…In contrast, fungi synthesize lysine via the ␣-aminoadipate pathway (66), and most, if not all, fungi contain the key enzymes of this pathway. Therefore, inhibition of fungal lysine biosynthesis has been assumed to be a possible antifungal drug target (43,64).…”

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Evaluation of Lysine Biosynthesis as an Antifungal Drug Target: Biochemical Characterization of Aspergillus fumigatus Homocitrate Synthase and Virulence Studies

2010

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Aspergillus fumigatus is the main cause of severe invasive aspergillosis. To combat this life-threatening infection, only limited numbers of antifungals are available. The fungal ␣-aminoadipate pathway, which is essential for lysine biosynthesis, has been suggested as a potential antifungal drug target. Here we reanalyzed the role of this pathway for establishment of invasive aspergillosis in murine models. We selected the first pathway-specific enzyme, homocitrate synthase (HcsA), for biochemical characterization and for study of its role in virulence. A. fumigatus HcsA was specific for the substrates acetyl-coenzyme A (acetyl-CoA) and ␣-ketoglutarate, and its activity was independent of any metal ions. In contrast to the case for other homocitrate synthases, enzymatic activity was hardly affected by lysine and gene expression increased under conditions of lysine supplementation. An hcsA deletion mutant was lysine auxotrophic and unable to germinate on unhydrolyzed proteins given as a sole nutrient source. However, the addition of partially purified A. fumigatus proteases restored growth, confirming the importance of free lysine to complement auxotrophy. In contrast to lysine-auxotrophic mutants from other fungal species, the mutant grew on blood and serum, indicating the existence of high-affinity lysine uptake systems. In agreement, although the virulence of the mutant was strongly attenuated in murine models of bronchopulmonary aspergillosis, virulence was partially restored by lysine supplementation via the drinking water. Additionally, in contrast to the case for attenuated pulmonary infections, the mutant retained full virulence when injected intravenously. Therefore, we concluded that inhibition of fungal lysine biosynthesis, at least for disseminating invasive aspergillosis, does not appear to provide a suitable target for new antifungals.

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Synthesis and Antifungal Properties of Compounds which Target the α‐Aminoadipate Pathway.

Abstract: For Abstract see ChemInform Abstract in Full Text.

Cited by 13 publications

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Growth rate of Aspergillus nidulans hyphae is independent of a prominent array of microtubules

Growth rate of Aspergillus nidulans hyphae is independent of a prominent array of microtubules

The lysine biosynthetic enzyme Lys4 influences iron metabolism, mitochondrial function and virulence in Cryptococcus neoformans

Evaluation of Lysine Biosynthesis as an Antifungal Drug Target: Biochemical Characterization of Aspergillus fumigatus Homocitrate Synthase and Virulence Studies

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