The Antifungal Echinocandin Caspofungin Acetate Kills Growing Cells of
            <i>Aspergillus fumigatus</i>
            In Vitro

Bowman, Joel; Hicks, Patricia Scott; Kurtz, Myra B.; Rosén, Harald; Schmatz, Dennis M.; Liberator, Paul; Douglas, Cameron M.

doi:10.1128/aac.46.9.3001-3012.2002

Cited by 293 publications

(204 citation statements)

References 39 publications

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“…without cross-resistance to existing antifungal agents, and therefore are effective against azole-resistant yeasts and moulds (Denning, 2003, Bennett, 2006Morrison, 2006). The echinocandins are fungicidal against yeasts but fungistatic against moulds, where they block the growing tips of hyphae (Bowman et al, 2002;Douglas, 2006). Echinocandin drugs are highly effective on biofilms (Bachmann et al, 2002b) but are less active against Zygomycetes, Cryptococcus neoformans or Fusarium spp.…”

Section: Echinocandin Antifungal Drugsmentioning

confidence: 99%

Resistance to echinocandin-class antifungal drugs

Perlin¹

2007

Drug Resistance Updates

455

400

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Invasive fungal infections cause morbidity and mortality in severely ill patients, and limited drug classes restrict treatment choices. The echinocandins drugs are the first new class of antifungal compounds that target the fungal cell wall by blocking β-1,3-D-glucan synthase. Elevated MIC values with occasional treatment failure have been reported for strains of Candida. Yet, an uncertain correlation exists between clinical failure and elevated MIC values for the echinocandin drugs. Fungi display several adaptive physiological mechanisms that result in elevated MIC values. However, resistance to echinocandin drugs among clinical isolates is associated with amino acid substitutions in two "hot-spot" regions of Fks1, the major subunit of glucan synthase. The mutations, yielding highly elevated MIC values, are genetically dominant and confer cross-resistance to all echinocandin drugs. Prominent Fks1 mutations decrease the sensitivity of glucan synthase for drug by one thousand-fold or more, and strains harboring such mutations may require a concomitant increase in drug to reduce fungal organ burdens in animal infection models. The Fks1-mediated resistance mechanism is conserved in a wide variety of Candida spp. and can account for intrinsic reduced susceptibility of certain species. Fks1 mutations confer resistance in both yeasts and moulds suggesting that this mechanism is pervasive in the fungal kingdom.

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Section: Echinocandin Antifungal Drugsmentioning

confidence: 99%

Resistance to echinocandin-class antifungal drugs

Perlin¹

2007

Drug Resistance Updates

455

400

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“…The two main causative agents of opportunistic fungal infections are the commensal polymorphic yeast Candida albicans and the saprophytic filamentous fungus Aspergillus fumigatus (38,51). Currently available antifungal drugs belong to three main classes: polyenes (e.g., amphotericin B) and azoles (e.g., fluconazole), both of which target fungal membranes (19,22), and the new echinocandin family (e.g., caspofungin), which targets the enzyme responsible for cell wall ␤(1,3)-glucan biosynthesis (2,23). However, systemic fungal infections are still associated with a high mortality, mainly due to the relative toxicity and side effects of antifungal drugs, in addition to often-late diagnosis and the emergence of resistance (15,19,49).…”

mentioning

confidence: 99%

Identification of Essential Genes in the Human Fungal Pathogen Aspergillus fumigatus by Transposon Mutagenesis

et al. 2003

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The opportunistic pathogen Aspergillus fumigatus is the most frequent cause of deadly airborne fungal infections in developed countries. In order to identify novel antifungal-drug targets, we investigated the genome of A. fumigatus for genes that are necessary for efficient fungal growth. An artificial A. fumigatus diploid strain with one copy of an engineered impala160 transposon from Fusarium oxysporum integrated into its genome was used to generate a library of diploid strains by random in vivo transposon mutagenesis. Among 2,386 heterozygous diploid strains screened by parasexual genetics, 1.2% had a copy of the transposable element integrated into a locus essential for A. fumigatus growth. Comparison of genomic sequences flanking impala160 in these mutants with that of the genome of A. fumigatus allowed the characterization of 20 previously uncharacterized A. fumigatus genes. Among these, homologues of genes essential for Saccharomyces cerevisiae growth have been identified, as well as genes that do not have homologues in other fungal species. These results confirm that heterologous transposition using the transposable element impala is a powerful tool for functional genomics in ascomycota, and they pave the way for defining the complete set of essential genes in A. fumigatus, the first step toward target-based development of new antifungal drugs.

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“…and have emerged as an important therapeutic option for candidiasis. By growth assays and in vivo studies, the echinocandians are fungistatic toward Aspergillus; however, vital dye studies indicate that caspofungin, for example, kills growing Aspergillus fumigatus (Bowman et al 2002). At this time, the echinocandins are considered a second-line salvage therapy for those infections.…”

Section: Current Antifungal Therapiesmentioning

confidence: 99%

“…Like all assays, these growth-inhibition assays have limitations and a number of these dramatically reduce its utility in antifungal drug discovery. First, the fact that many pathogenic fungi grow as filaments (e.g., Aspergillus) leads to a poor correlation between organism growth and optical density (Bowman et al 2002). Second, traditional growth assays are not useful for identifying molecules active against fungal biofilms, a medically important growth phase of these pathogens (Pierce et al 2008;LaFleur et al 2011;Srinivasan et al 2013).…”

Section: Antifungal Drug Discovery: Process and New Approachesmentioning

confidence: 99%

Antifungal Drug Development: Challenges, Unmet Clinical Needs, and New Approaches

Roemer

Krysan

2014

Cold Spring Harbor Perspectives in Medicine

469

353

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Invasive, life-threatening fungal infections are an important cause of morbidity and mortality, particularly for patients with compromised immune function. The number of therapeutic options for the treatment of invasive fungal infections is quite limited when compared with those available to treat bacterial infections. Indeed, only three classes of molecules are currently used in clinical practice and only one new class of antifungal drugs has been developed in the last 30 years. Here we summarize the unmet clinical needs of current antifungal therapy, discuss challenges inherent to antifungal drug discovery and development, and review recent developments aimed at addressing some of these challenges.

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The Antifungal Echinocandin Caspofungin Acetate Kills Growing Cells of Aspergillus fumigatus In Vitro

Cited by 293 publications

References 39 publications

Resistance to echinocandin-class antifungal drugs

Resistance to echinocandin-class antifungal drugs

Identification of Essential Genes in the Human Fungal Pathogen Aspergillus fumigatus by Transposon Mutagenesis

Antifungal Drug Development: Challenges, Unmet Clinical Needs, and New Approaches

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