Discovery of Novel Antifungal (1,3)-β-d-Glucan Synthase Inhibitors

@article{Onishi2000DiscoveryON,
  title={Discovery of Novel Antifungal (1,3)-$\beta$-d-Glucan Synthase Inhibitors},
  author={J. C. Onishi and Maria S. Meinz and J R Thompson and James E. Curotto and Sarah Dreikorn and Mark J Rosenbach and Cameron M. Douglas and George K. Abruzzo and Amy M. Flattery and Lingsheng Kong and Angeles Cabello and Francisca Vicente and Fernando Peláez and M T D{\'i}ez and Isabella Martin and G Bills and Robert A. Giacobbe and Anne W. Dombrowski and Robert E. Schwartz and Sandra A. Morris and Guy H. Harris and A. Tsipouras and Kenneth E. Wilson and Myra Berman Kurtz},
  journal={Antimicrobial Agents and Chemotherapy},
  year={2000},
  volume={44},
  pages={368 - 377}
}
ABSTRACT The increasing incidence of life-threatening fungal infections has driven the search for new, broad-spectrum fungicidal agents that can be used for treatment and prophylaxis in immunocompromised patients. Natural-product inhibitors of cell wall (1,3)-β-d-glucan synthase such as lipopeptide pneumocandins and echinocandins as well as the glycolipid papulacandins have been evaluated as potential therapeutics for the last two decades. As a result, MK-0991 (caspofungin acetate; Cancidas), a… 
Discovery of a Novel Class of Orally Active Antifungal β-1,3-d-Glucan Synthase Inhibitors
TLDR
A screen for antifungal bioactivities combined with mechanism-of-action studies identified a class of piperazinyl-pyridazinone compounds that target β-1,3-glucan synthase that exhibited in vitro activity comparable, and in some cases superior, to the echinocandins.
Discovery of a Small-Molecule Inhibitor of β-1,6-Glucan Synthesis
TLDR
Genetic analysis of a D75-4590-resistant mutant of S. cerevisiae indicated that its primary target was Kre6p, which is considered to be one of the β-1,6-glucan synthases, and results strongly suggest that D75,4590 is a specific inhibitor of β- 1,6, glucan synthesis.
New β-glucan inhibitors as antifungal drugs
TLDR
The Merck compound MK-3118 is an analog of the natural product enfumafungin that, in particular, shows promise as it has a spectrum of activity comparable with caspofungin but has the advantageous property of oral bioavailability.
Cell wall active antifungal agents
The recent American approval of Cancidas™, a semi-synthetic echinocandin, for salvage treatment of aspergillosis has demonstrated that the cell wall is a clinically viable target for treating fungal
Update on antifungals targeted to the cell wall: focus on β-1,3-glucan synthase inhibitors
TLDR
Cell wall-acting antifungals are inherently selective and fungicidal, features that make them particularly attractive for clinical development, and three classes of such compounds, targeted respectively to chitin synthase, echinocandins, β-1,3-glucan synthase and mannoproteins, have entered clinical development.
Discovery and characterization of ß-1,6-glucan inhibitors
  • A. Kitamura
  • Biology
    Expert opinion on drug discovery
  • 2010
TLDR
The β-1,6-glucan inhibitors are considered to be promising candidates for new antifungal drugs which could give valuable options in a clinical setting, although their usage may be limited because of their fungistatic action and limited spectrum.
Novel orally active inhibitors of β-1,3-glucan synthesis derived from enfumafungin.
MK-5204: An orally active β-1,3-glucan synthesis inhibitor.
...
1
2
3
4
5
...

References

SHOWING 1-10 OF 81 REFERENCES
Increased antifungal activity of L-733,560, a water-soluble, semisynthetic pneumocandin, is due to enhanced inhibition of cell wall synthesis
TLDR
Results support the notion that the enhanced antifungal activity of L-733,560 is achieved by superior inhibition of glucan synthesis and not by nonspecific membrane effects or a second mode of action.
Lipopeptide inhibitors of fungal glucan synthase.
  • M. Kurtz, C. Douglas
  • Biology
    Journal of medical and veterinary mycology : bi-monthly publication of the International Society for Human and Animal Mycology
  • 1997
TLDR
The echinocandins and pneumocandin are lipopeptide antifungal agents that inhibit the synthesis of 1,3-beta-D-glucan, an essential cell wall homopolysaccharide found in many pathogenic fungi and the application to Candida albicans and other pathogenic fungus are discussed in this review.
Identification of the FKS1 gene of Candida albicans as the essential target of 1,3-beta-D-glucan synthase inhibitors
TLDR
It is concluded that C. albicans strains CAI4R1, NR2, and NR4 are heterozygous for a dominant or semidominant pneumocandin resistance mutation at CaFKS1, and CaFks1p is a target of the echinocandins.
A Glucan Synthase FKS1 Homolog inCryptococcus neoformans Is Single Copy and Encodes an Essential Function
TLDR
The results of this analysis suggest that the C. neoformans FKS1 gene is essential for viability, and a generalized method to evaluate the essentiality of genes in Cryptococcus was developed and applied to the F KS1 gene.
Evaluation of the echinocandin antifungal MK-0991 (L-743,872): efficacies in mouse models of disseminated aspergillosis, candidiasis, and cryptococcosis
TLDR
MK-0991 is a potent, parenterally administered therapeutic agent against disseminated candidiasis and aspergillosis that warrants further investigation in human clinical trials.
A Saccharomyces cerevisiae mutant with echinocandin-resistant 1,3-beta-D-glucan synthase
TLDR
A novel, potent, semisynthetic pneumocandin, L-733,560, was used to isolate a resistant mutant in Saccharomyces cerevisiae and it is proposed that the etg1-1 mutant gene encodes a subunit of the 1,3-beta-D-glucan synthase complex.
Characterization of echinocandin-resistant mutants of Candida albicans: genetic, biochemical, and virulence studies
TLDR
The virulence of the spontaneous mutants was unimpaired in a mouse model of disseminated candidiasis, while M-2 and CA-2 were 2 orders of magnitude less virulent than their parent strains, suggesting that these resistant mutants may have alterations in glucan synthase.
Current and Emerging Azole Antifungal Agents
TLDR
Present and future uses of the currently available azole antifungal agents in the treatment of systemic and superficial fungal infections are described and a brief overview of the current status of in vitro susceptibility testing and the growing problem of clinical resistance to the azoles is provided.
Characterization of (1,3)-beta-glucan synthase in Candida albicans: microsomal assay from the yeast or mycelial morphological forms and a permeabilized whole-cell assay.
TLDR
The addition of detergent during mechanical breakage of yeast cells dramatically improved glucan synthase stability and activity, and Brij-35 significantly stabilized the enzyme, yielding a half-life of 5.6 d at 4 degrees C, compared with 0.9 d without detergent.
L-687,781, a new member of the papulacandin family of beta-1,3-D-glucan synthesis inhibitors. I. Fermentation, isolation, and biological activity.
A new beta-1,3-D-glucan synthesis inhibitor, L-687,781 is produced by the cultivation of Dictyochaeta simplex ATCC 20960. L-687,781 exhibits potent in vitro antifungal activity as well as
...
1
2
3
4
5
...