n-n-dimethylpradimicin-fa-2 and Mycoses

Due to the limit of available treatments and the emergence of drug resistance in the clinic, invasive fungal infections are an intractable problem with high morbidity and mortality. The cell wall, as a fungi-specific structure, is an appealing target for the discovery and development of novel and low-toxic antifungal agents. In an attempt to accelerate the discovery of novel cell wall targeted drugs, this Perspective will provide a comprehensive review of the progress made to date on the development of fungal cell wall inhibitors. Specifically, this review will focus on the targets, discovery process, chemical structures, antifungal activities, and structure-activity relationships. Although two types of cell wall antifungal agents are clinically available or in clinical trials, it is still a long way for the other cell wall targeted inhibitors to be translated into clinical applications. Future efforts should be focused on the identification of inhibitors against novel conserved cell wall targets.

Topics: Antifungal Agents; Cell Wall; Drug Discovery; Fungi; GPI-Linked Proteins; Humans; Mannans; Mycoses; Triterpenes

BMY-28864, a water-soluble pradimicin derivative, had potent in vitro activity against a wide variety of fungi, including those associated with deep-seated mycosis; it inhibited the growth of standard strains and clinical isolates at concentrations of 12.5 micrograms/ml or less. At the MIC or higher concentrations, BMY-28864 was fungicidal for Candida albicans under both growing and nongrowing conditions. BMY-28864 expressed fungicidal activity only in the presence of Ca2+, and its activity was totally diminished when ethylene glycol-bis(2-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA), a Ca2+ chelator, was added to the test medium. The effectiveness of intravenously administered BMY-28864 in vivo was examined and compared with that of amphotericin B in mouse models of fungal infections. Both normal and cyclophosphamide-treated immunosuppressed mice infected with C. albicans, Cryptococcus neoformans, or Aspergillus fumigatus responded to therapy with BMY-28864 (50% protective doses of 17, 18, and 37 mg/kg of body weight in normal mice and of 32, 35, and 51 mg/kg in cyclophosphamide-treated mice, respectively). Lethal lung infections were also established with C. albicans or A. fumigatus in cyclophosphamide-treated mice. The 50% protective doses of BMY-28864 were 15 and 23 mg/kg per dose against C. albicans and A. fumigatus, respectively. The immunosuppression induced by intraperitoneal administration of 200 mg of cyclophosphamide per kg lasted for 5 days, and total recovery was observed by day 7.

Topics: Amphotericin B; Animals; Anthracyclines; Antibiotics, Antineoplastic; Antifungal Agents; Calcium; Culture Media; Egtazic Acid; Fungi; Immunosuppression Therapy; Lung Diseases, Fungal; Male; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; Mycoses

Three N,N-dimethyl pradimicins were synthesized by reductive alkylation of pradimicins A, E and FA-2 and evaluated for antifungal activity, water solubility and acute toxicity in mice. They showed in vitro antifungal activity superior to pradimicin A. N,N-Dimethylpradimicins E and FA-2 showed great improvement in water solubility and animal tolerance. N,N-Dimethylpradimicin FA-2 was effective in 3 experimental in vivo fungal infection models.

Topics: Alkylation; Animals; Anthracyclines; Antibiotics, Antineoplastic; Antifungal Agents; Candida; Disease Models, Animal; Drug Tolerance; Fungi; Male; Mice; Mice, Inbred ICR; Molecular Structure; Mycoses; Oxidation-Reduction; Solubility