Echinocandins: the newest class of antifungals.
ABSTRACT To review the mechanism of action, antifungal spectrum of activity, pharmacodynamics, pharmacokinetics, clinical efficacy, and safety of the echinocandins.
A MEDLINE search (1982-May 2009) was conducted for articles published in the English language using the key words caspofungin, micafungin, anidulafungin, and echinocandins.
Medicinal chemistry, in vitro, and animal studies, as well as human trials were reviewed for information on the pharmacodynamics, pharmacokinetics, efficacy, and safety of each echinocandin. Clinical trials were reviewed and included to compare and contrast the available echinocandins.
Three echinocandin antifungal agents are currently approved for use in the US: caspofungin, micafungin, and anidulafungin. The echinocandins have a unique mechanism of action, inhibiting beta-(1,3)-D-glucan synthase, an enzyme that is necessary for the synthesis of an essential component of the cell wall of several fungi. The echinocandins display fungistatic activity against Aspergillus spp. and fungicidal activity against most Candida spp., including strains that are fluconazole-resistant. The echinocandins have been shown to be efficacious for the treatment of esophageal candidiasis, candidemia, and invasive candidiasis. In addition, caspofungin has demonstrated efficacy as empiric treatment of febrile neutropenia and salvage therapy for the treatment of invasive aspergillosis, and it is the only echinocandin approved for use in pediatric patients. Micafungin is the only echinocandin approved for use as prophylaxis against Candida infections in patients undergoing hematopoietic stem cell transplantation. Overall, resistance to echinocandins is still rare, and all agents are well tolerated, with similar adverse effect profiles and few drug-drug interactions.
Echinocandins, the newest addition to the arsenal of antifungals, offer potential advantages over other classes of agents. Clinicians should assess their distinguishing characteristics, including route of metabolism, drug interaction profile, and approved indications for use, when determining which agent to include on a formulary.
Article: Safety and efficacy of liposomal amphotericin B for the empirical therapy of invasive fungal infections in immunocompromised patients.[show abstract] [hide abstract]
ABSTRACT: Liposomal amphotericin B is a "true" liposomal formulation of amphotericin B with greatly reduced nephrotoxicity and minimal infusion-related toxicity. This broad spectrum polyene is well tolerated and effective against most invasive fungal infections. In view of the current limitations on diagnostic capability of invasive fungal infections, most clinicians are often compelled to use antifungal drugs in an empiric manner; liposomal amphotericin B continues to play an important role in the empiric management of invasive fungal infections, despite the recent availability of several other drugs in the azole and echinocandin classes.Infection and Drug Resistance 01/2012; 5:9-16.
Article: High-throughput screen for identifying small molecules that target fungal zinc homeostasis.[show abstract] [hide abstract]
ABSTRACT: Resistance to traditional antifungal drugs has increased significantly over the past three decades, making identification of novel antifungal agents and new targets an emerging priority. Based on the extraordinary zinc requirement of several fungal pathogens and their well-established sensitivity to zinc deprivation, we developed an efficient cell-based screen to identify new antifungal drugs that target the zinc homeostasis machinery. The screen is based on the zinc-regulated transcription factor Zap1 of Saccharomyces cerevisiae, which regulates transcription of genes like the high-affinity zinc transporter ZRT1. We generated a genetically modified strain of S. cerevisae that reports intracellular zinc deficiency by placing the coding sequence of green fluorescent protein (GFP) under the control of the Zap1-regulated ZRT1 promoter. After showing that the GFP fluorescence signal correlates with low intracellular zinc concentrations in this strain, a protocol was developed for screening small-molecule libraries for compounds that induce Zap1-dependent GFP expression. Comparison of control compounds and known modulators of metal metabolism from the library reveals a robust screen (Z' = 0.74) and validates this approach to the discovery of new classes of antifungal compounds that interfere with the intracellular zinc homeostasis. Given that growth of many pathogenic organisms is significantly impaired by zinc limitation; these results identify new types of antifungal drugs that target critical nutrient acquisition pathways.PLoS ONE 01/2011; 6(9):e25136. · 4.09 Impact Factor
Article: Ste11p MEKK signals through HOG, mating, calcineurin and PKC pathways to regulate the FKS2 gene.[show abstract] [hide abstract]
ABSTRACT: The S. cerevisiae MAPKKK Ste11p, a homologue of mammalian MEKK1, regulates three MAPK cascades for mating, invasive growth and osmotic stress and provides functions that are additive with the cell wall integrity pathway. Cell wall integrity requires the FKS2 gene that encodes a stress-induced alternative subunit of beta-1, 3 glucan synthase that is the target of echinocandin 1,3- beta glucan synthase inhibitors. The major signal transduction pathways that activate transcription of the FKS2 gene include the cell wall integrity and calcineurin pathways, and the Ste11p pathway. Here it is shown that catalytically active Ste11p regulates FKS2-lacZ reporter genes through Ste12, calcineurin/Crz1p- and PKC pathways and the high osmolarity pathway. Ste11p stimulated the cell wall integrity MAPK Mpk1p (Erk5 homologue) and FKS2 independently of the mating pathway. Ste11p regulated FKS2 through all known and putative substrates: Pbs2p MAPKK, Ste7 MAPKK, Cmk2p calmodulin dependent kinase and Ptk2p kinase. Ste11p increased the expression level of Cmk2p through transcription-dependent and -independent mechanisms. The data suggest Ste11p regulates the FKS2 gene through all its known and putative downstream kinase substrates (Pbs2p, Ste7p, Cmk2p, and Ptk2p) and separately through Mpk1p MAPK. The patterns of control by Ste11p targets revealed novel functional linkages, cross-regulation, redundancy and compensation.BMC Molecular Biology 11/2011; 12:51. · 2.86 Impact Factor