papulacandin-b and nikkomycin

A number of substances that directly or indirectly affect the cell walls of fungi have been identified. Those that actively interfere with the synthesis or degradation of polysaccharide components share the property of being produced by soil microbes as secondary metabolites. Compounds specifically interfering with chitin or beta-glucan synthesis have proven effective in studies of preclinical models of mycoses, though they appear to have a restricted spectrum of coverage. Semisynthetic derivatives of some of the natural products have offered improvements in activity, toxicology, or pharmacokinetic behavior. Compounds which act on the cell wall indirectly or by a secondary mechanism of action, such as the azoles, act against diverse fungi but are usually fungistatic in nature. Overall, these compounds are attractive candidates for further development.

Topics: Aminoglycosides; Amphotericin B; Animals; Anthracyclines; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Cell Wall; Chitin; Echinocandins; Fungal Proteins; Fungi; Glucans; Mice; Mycoses; Peptides; Peptides, Cyclic; Pyrimidine Nucleosides

The design and synthesis of several beta-1,4-galactosyltransferase inhibitors are reported. Mimics of the pyrophosphate-Mn2+ complex were the focus of the design. Malonic, tartaric, and monosaccharide moieties were used as replacements of the pyrophosphate moiety, and galactose or azasugars with potent galactosidase inhibitory activity were used as the 'donor' component. Compound 6, in which glucose was used as the pyrophosphate-Mn2+ complex mimic and galactose as the 'donor' component, showed the best inhibitory activity towards the transferase with a Ki of 119.6 microM.

Topics: Aminoglycosides; Anti-Bacterial Agents; Antifungal Agents; Antiviral Agents; Binding Sites; Diphosphates; Enzyme Inhibitors; Fucosyltransferases; Malonates; Manganese; Monosaccharides; N-Acetyllactosamine Synthase; Pyrimidine Nucleosides; Substrate Specificity; Tartrates; Tunicamycin

Incorporation of polysaccharides into the walls of regenerating protoplasts of Candida albicans was followed in the presence of papulacandin B, tunicamycin and nikkomycin. With the first drug, chitin was incorporated normally whereas incorporation of glucans and mannoproteins was significantly decreased. Tunicamycin decreased incorporation of all wall polymers when added at the beginning of the regeneration process but blocked only mannan and alkali-insoluble glucan incorporation when added after 5 h. Nikkomycin inhibited chitin synthesis, and the walls formed by the protoplasts were enriched in alkali-soluble glucan. Pulse-chase experiments suggested that a precursor-product relationship between the alkali-soluble and alkali-insoluble glucans existed in the wall. The results obtained with the antibiotics were confirmed and extended by cytological studies using wheat-germ agglutinin labelled with colloidal gold and concanavalin A-ferritin as specific markers of chitin and mannoproteins respectively. The results support the idea that regeneration of walls by protoplasts occurs in two steps: firstly, a chitin microfibrillar skeleton is formed, and in a later step glucan-mannoprotein complexes are added to the growing structure. The chitin skeleton probably allows the orderly spatial arrangement of the other polymers giving rise to the regenerated cell wall.

Topics: Aminoglycosides; Anti-Bacterial Agents; Antifungal Agents; Candida albicans; Cell Wall; Microscopy, Electron; Polysaccharides, Bacterial; Protoplasts; Tunicamycin

Combinations of nikkomycin X (NX) or nikkomycin Z (NZ), known inhibitors of chitin synthesis in fungi, together with papulacandin B (PB), an inhibitor of beta-glucan synthesis, were tested for synergistic activity against four isolates of Candida albicans by using the broth microdilution checkerboard technique and a method to assess the regeneration of cell wall material in protoplasts. The construction of isobolograms from the data generated by the checkerboard determinations revealed a synergistic effect for the two classes of compounds against all strains. The combination of NX and PB was more effective than the combination of NZ and PB, perhaps reflecting the lower Ki value of NX. While the presence of NX and NZ reduced chitin synthesis, as determined by staining with calcofluor white and assaying with a microfluorimeter, cells treated with PB demonstrated an increased synthesis of chitin. Protoplast regeneration experiments using similar concentrations of the two classes of compounds resulted in comparable findings. The combination of NX and PB resulted in a greater inhibition of chitin synthesis than did equivalent combinations of NZ and PB. These data suggest that combinations of agents active against cell wall synthesis in fungi may prove more useful as chemotherapeutic agents than such compounds used singly.

Topics: Aminoglycosides; Anti-Bacterial Agents; Antifungal Agents; Candida albicans; Drug Synergism; Glycosides; Microbial Sensitivity Tests; Microscopy, Fluorescence; Nucleosides; Protoplasts