In Vitro Antifungal Activities of D11-2040, a .BETA.-1,6-Glucan Inhibitor, with or without Currently Available Antifungal Drugs

Kitamura, Akihiro; Someya, Kazuhiko; Okumura, Ryo; Hata, Masato; Takeshita, Hiroshi; Nakajima, Riichiro

doi:10.1248/bpb.33.192

Cited by 19 publications

(14 citation statements)

References 22 publications

(27 reference statements)

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“…Recent work by others has identified specific inhibitors that reduce ␤-1,6 glucan synthase activity (43)(44)(45). Such agents represent a potential antifungal strategy capable of inhibiting ␤-1,6 glucan synthase activity in vitro, as well as in vivo (43)(44)(45).…”

Section: Resultsmentioning

confidence: 99%

“…The absorbance at 450 nm was measured in a VersaMax plate reader (Molecular Devices, Sunnyvale, CA), and standards were plotted using the 4-parameter curve-fitting setting of the SoftMax Pro software. Additional assays were performed in the presence of newly described ␤-1,6 glucan synthase inhibitors (0.06 g/ml each) that inhibit ␤-1,6 glucan synthesis in yeast and Candida albicans (41)(42)(43)(44)(45).…”

Section: Methodsmentioning

confidence: 99%

“…Kitamura and colleagues recently described a novel cell-based assay to screen large numbers of yeast cell wall component inhibitors, including those that suppress ␤-1,6 glucan synthesis (44). Several pyridobenzimidazole derivatives with activities against S. cerevisiae kre6 activity were uncovered (44,45). These ␤-1,6 glucan inhibitors were further demonstrated to possess activity against Candida spp., C. neoformans, and Aspergillus fumigatus (43)(44)(45).…”

Section: Fig 8 Pmentioning

confidence: 99%

“…Several pyridobenzimidazole derivatives with activities against S. cerevisiae kre6 activity were uncovered (44,45). These ␤-1,6 glucan inhibitors were further demonstrated to possess activity against Candida spp., C. neoformans, and Aspergillus fumigatus (43)(44)(45).…”

Section: Fig 8 Pmentioning

confidence: 99%

“…Therefore, this new class of cell wall inhibitors represents potential new antifungal medications, which may be used either alone or in conjunction with other antifungal agents. Indeed, against C. albicans, the ␤-1,6 glucan inhibitor D11-2040 has been shown to have synergistic activity when administered along with other antifungal agents (45).…”

Section: Fig 8 Pmentioning

confidence: 99%

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Evidence for Proinflammatory β-1,6 Glucans in the Pneumocystis carinii Cell Wall

et al. 2015

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Inflammation is a major cause of respiratory impairment during Pneumocystis pneumonia. Studies support a significant role for cell wall ␤-glucans in stimulating inflammatory responses. Fungal ␤-glucans are comprised of D-glucose homopolymers containing ␤-1,3-linked glucose backbones with ␤-1,6-linked glucose side chains. Prior studies in Pneumocystis carinii have characterized ␤-1,3 glucan components of the organism. However, recent investigations in other organisms support important roles for ␤-1,6 glucans, predominantly in mediating host cellular activation. Accordingly, we sought to characterize ␤-1,6 glucans in the cell wall of Pneumocystis and to establish their activity in lung cell inflammation. Immune staining revealed specific ␤-1,6 localization in P. carinii cyst walls. Homology-based cloning facilitated characterization of a functional P. carinii kre6 (Pckre6) ␤-1,6 glucan synthase in Pneumocystis that, when expressed in kre6-deficient Saccharomyces cerevisiae, restored cell wall stability. Recently synthesized ␤-1,6 glucan synthase inhibitors decreased the ability of isolated P. carinii preparations to generate ␤-1,6 carbohydrate. In addition, isolated ␤-1,6 glucan fractions from Pneumocystis elicited vigorous tumor necrosis factor alpha (TNF-␣) responses from macrophages. These inflammatory responses were significantly dampened by inhibition of host cell plasma membrane microdomain function. Together, these studies indicate that ␤-1,6 glucans are present in the P. carinii cell wall and contribute to lung cell inflammatory activation during infection. P neumocystis organisms are opportunistic fungi that produce significant morbidity and mortality in immunocompromised hosts, with infection-related fatalities ranging between 10% and 45% (1). Pneumocystis jirovecii is the species known to infect humans, while Pneumocystis carinii represents the parallel species studied widely in rodents (2). Pneumocystis pneumonia remains a significant cause of mortality during AIDS, despite highly active antiretroviral therapy (3-5). Severe Pneumocystis pneumonia is characterized by intense lung inflammation involving CD8 ϩ cells and neutrophils, impairing gas exchange (6-9).The P. carinii cell walls contain abundant ␤-glucan molecules (10). Fungal cell wall ␤-glucans are homopolymers of D-glucose consisting of ␤-1,3 core chains with variable numbers of ␤-1,6 glucose side chains. The variable inflammatory activities of different glucan preparations have been postulated to be related to the relative amounts and configurations of these two major structures (␤-1,3 versus ␤-1,6) (11). Almost all of the initial studies in fungi have largely focused on unfractionated glucans (10). In fact, all prior studies in P. carinii previously utilized only unfractionated ␤-1,3/␤-1,6 glucans. Interestingly, recent investigations in Saccharomyces cerevisiae indicate major roles for ␤-1,6 glucans in strongly mediating cellular activation and inflammation (11). Our investigations of unfractionated P. carinii ␤-glucans indicate that innate ...

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Fig 8 Pmentioning

confidence: 99%

Section: Fig 8 Pmentioning

confidence: 99%

Section: Fig 8 Pmentioning

confidence: 99%

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Evidence for Proinflammatory β-1,6 Glucans in the Pneumocystis carinii Cell Wall

et al. 2015

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New Cell Wall-Affecting Antifungal Antibiotics

Ribas

Durán

Cortés

2013

Antimicrobial Compounds

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Fungi have emerged worldwide as increasingly frequent causes of healthcareassociated infections. Invasive fungal infections can be life-threatening. However, the number of antifungal agents available and their use in therapy is very limited. Recently, a new family of specific fungal cell wall synthesis inhibitors has emerged as an alternative antifungal therapy and is gaining increasing relevance yearly. The cell wall is a multilayer dynamic structure, essential to the integrity and shape of the fungal cell, whose function is to counteract the osmotic forces that could otherwise produce fungal cell lysis. The cell wall is absent in nonfungal cells, therefore representing a useful target in discovering selective drugs for the treatment of fungal infections without causing toxicity in the host. Although fungi exhibit a considerable diversity in their cell wall structure, all present β(1,3)-, β(1,6)-and α(1,3)-glucans, chitin, and mannoproteins as their major cell wall components. Three different cell wall synthesis inhibitors of the lipopeptide family of echinocandins, named caspofungin, micafungin and anidulafungin, are commercially-available and new classes of cell wall synthesis inhibitors are emerging. This review provides an overview of what is so far known about the different classes of cell wall-affecting antifungal agents and their mechanism of action, offering new alternatives with clinical potential.

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Overview of Alternaria alternata Membrane Proteins

Wang

Zhao

et al. 2020

Indian J Microbiol

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In Vitro Antifungal Activities of D11-2040, a .BETA.-1,6-Glucan Inhibitor, with or without Currently Available Antifungal Drugs

Cited by 19 publications

References 22 publications

Evidence for Proinflammatory β-1,6 Glucans in the Pneumocystis carinii Cell Wall

Evidence for Proinflammatory β-1,6 Glucans in the Pneumocystis carinii Cell Wall

New Cell Wall-Affecting Antifungal Antibiotics

Overview of Alternaria alternata Membrane Proteins

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