Recent Advances in Antifungal Agents

Lóránd, Tamás; Kocsis, Béla

doi:10.2174/138955707781662672

Cited by 34 publications

(11 citation statements)

References 60 publications

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“…This is of relevance for considering potential teratogenic side effects of lipid lowering drugs but also of antimicrobial agents that often target sterol synthesis. [42][43][44][45] We conclude that LBR missense mutations in the transmembrane domain can abolish sterol reductase activity, thereby causing lethal Greenberg dysplasia but not Pelger anomaly. This finding separates the metabolic from the structural function of quality could affect farnesylation, oxysterols, steroid hormones, bile acids, vitamin D, hedgehog signaling, modification of other nuclear components as well as cytoplasmatic and nuclear lipid signaling.…”

Section: Nucleusmentioning

confidence: 79%

Mutations causing Greenberg dysplasia but not Pelger anomaly uncouple enzymatic from structural functions of a nuclear membrane protein

Clayton

Fischer

Mann

et al. 2010

Nucleus

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The lamin B receptor (LBR) is an inner nuclear membrane protein with a structural function interacting with chromatin and lamins, and an enzymatic function as a sterol reductase. Heterozygous LBR mutations cause nuclear hyposegmentation in neutrophils (Pelger anomaly), while homozygous mutations cause prenatal death with skeletal defects and abnormal sterol metabolism (Greenberg dysplasia). It has remained unclear whether the lethality in Greenberg dysplasia is due to cholesterol defects or altered nuclear morphology.To answer this question we characterized two LBR missense mutations and showed that they cause Greenberg dysplasia. Both mutations affect residues that are evolutionary conserved among sterol reductases. In contrast to wildtype LBR, both mutations failed to rescue C14 sterol reductase deficient yeast, indicating an enzymatic defect. We found no Pelger anomaly in the carrier parent excluding marked effects on nuclear structure. We studied Lbr in mouse embryos and demonstrate expression in skin and the developing skeletal system consistent with sites of histological changes in Greenberg dysplasia. Unexpectedly we found in disease-relevant cell types not only nuclear but also cytoplasmatic LBR localization. The cytoplasmatic LBR staining co-localized with ER-markers and is thus consistent with the sites of endogeneous sterol synthesis.We conclude that LBR missense mutations can abolish sterol reductase activity, causing lethal Greenberg dysplasia but not Pelger anomaly. The findings separate the metabolic from the structural function and indicate that the sterol reductase activity is essential for human intrauterine development. ResultsWe studied three fetuses that all fulfilled the clinical criteria of Greenberg dysplasia, namely intrauterine growth retardation, massive generalized edema (hydrops), extreme shortening of long bones (tetrabrachymelia) with a moth-eaten appearance of tubular bones, ectopic calcification centers and a narrow thorax (Fig. 1A, Suppl. Table 1). Detailed clinical examination was obtained from fetus A; fetus B has been described previously. 25Sterol analyses were performed in muscle tissue of fetus B and revealed the abnormal sterol metabolite 5α-cholest-8,14-dien-3β-ol, 25 that was previously shown to be associated with Greenberg dysplasia.18 Sterol analysis was not available for the other two fetuses.Sequence analysis revealed frameshift and missense mutations in the LBR gene. We sequenced LBR and identified mutations in all three families (Fig. 1B, sequence traces and segregation in Suppl. Fig. 1A). Fetus A showed a homozygous frameshift mutation c.1492delT that is predicted to change residues 468 to 474 and to create a premature stop in codon 475 (p.Y468TfsX475). Fetus B revealed two different mutations, c.32delTGGT and c.1748G>A. The first is a deletion of 4 base pairs causing a frame shift with subsequent premature stop in codon 24 (p.V11EfsX24). The second is a missense mutation replacing arginine by glutamine at residue 583 (R583Q). Both parents of fetus C were carrie...

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Section: Nucleusmentioning

confidence: 79%

Mutations causing Greenberg dysplasia but not Pelger anomaly uncouple enzymatic from structural functions of a nuclear membrane protein

Clayton

Fischer

Mann

et al. 2010

Nucleus

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“…In addition, the use of inhibitors from other steps of sterol biosynthesis is an alternative approach to the development of new chemotherapeutic agents. Several inhibitors of the mevalonate and isoprenoid pathways, as well inhibitors of the steps exclusively involved in ergosterol biosynthesis, have been studied against fungi [23] and parasitic protozoa [24]. For example, fluvastatin, a synthetic 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor, developed as a cholesterol-lowering agent, has a synergistic and fungicidal effect in combination with fluconazole and itraconazole against C. albicans , C. tropicalis , C. parapsilosis , and Cryptococcus neoformans , including fluconazole-resistant strains [25].…”

Section: Discussionmentioning

confidence: 99%

Synthetic arylquinuclidine derivatives exhibit antifungal activity against Candida albicans, Candida tropicalis and Candida parapsilopsis

Ishida

Rodrigues

Cammerer

et al. 2011

Ann Clin Microbiol Antimicrob

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BackgroundSterol biosynthesis is an essential pathway for fungal survival, and is the biochemical target of many antifungal agents. The antifungal drugs most widely used to treated fungal infections are compounds that inhibit cytochrome P450-dependent C14α-demethylase (CYP51), but other enzymes of this pathway, such as squalene synthase (SQS) which catalyses the first committed step in sterol biosynthesis, could be viable targets. The aim of this study was to evaluate the antifungal activity of SQS inhibitors on Candida albicans, Candida tropicalis and Candida parapsilopsis strains.MethodsTen arylquinuclidines that act as SQS inhibitors were tested as antiproliferative agents against three ATCC strains and 54 clinical isolates of Candida albicans, Candida tropicalis and Candida parapsilopsis. Also, the morphological alterations induced in the yeasts by the experimental compounds were evaluated by fluorescence and transmission electron microscopy.ResultsThe most potent arylquinuclidine derivative (3-[1'-{4'-(benzyloxy)-phenyl}]-quinuclidine-2-ene) (WSP1267) had a MIC50 of 2 μg/ml for all species tested and MIC90 varying from 4 μg/ml to 8 μg/ml. Ultrathin sections of C. albicans treated with 1 μg/ml of WSP1267 showed several ultrastructural alterations, including (a) loss of cell wall integrity, (b) detachment of the plasma membrane from the fungal cell wall, (c) accumulation of small vesicles in the periplasmic region, (d) presence of large electron-dense vacuoles and (e) significantly increased cell size and cell wall thickness. In addition, fluorescence microscopy of cells labelled with Nile Red showed an accumulation of lipid droplets in the cytoplasm of treated yeasts. Nuclear staining with DAPI revealed the appearance of uncommon yeast buds without a nucleus or with two nuclei.ConclusionTaken together, our data demonstrate that arylquinuclidine derivatives could be useful as lead compounds for the rational synthesis of new antifungal drugs.

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“…The echinocandins are an antimicrobial peptide family sourced from Aspergillus nidulans that includes the peptides anidulafungin caspofungin, and micafungin [201]. They have been shown to inhibit β-(1,3)-glucan synthase, an enzyme responsible for the production of the essential fungal cell wall component β-(1,3)-glucan [202–204]. …”

Section: Mechanism Of Action Of Antimicrobial Peptidesmentioning

confidence: 99%

The Potential of Antimicrobial Peptides as Biocides

Laverty¹,

Gorman

Gilmore

2011

IJMS

149

121

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Antimicrobial peptides constitute a diverse class of naturally occurring antimicrobial molecules which have activity against a wide range of pathogenic microorganisms. Antimicrobial peptides are exciting leads in the development of novel biocidal agents at a time when classical antibiotics are under intense pressure from emerging resistance, and the global industry in antibiotic research and development stagnates. This review will examine the potential of antimicrobial peptides, both natural and synthetic, as novel biocidal agents in the battle against multi-drug resistant pathogen infections.

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Recent Advances in Antifungal Agents

Cited by 34 publications

References 60 publications

Mutations causing Greenberg dysplasia but not Pelger anomaly uncouple enzymatic from structural functions of a nuclear membrane protein

Mutations causing Greenberg dysplasia but not Pelger anomaly uncouple enzymatic from structural functions of a nuclear membrane protein

Synthetic arylquinuclidine derivatives exhibit antifungal activity against Candida albicans, Candida tropicalis and Candida parapsilopsis

The Potential of Antimicrobial Peptides as Biocides

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