Papulacandin B: an Inhibitor of Glucan Synthesis in Yeast Spheroplasts

Abstract

Papulacandin B, the main component of a series of antibiotics produced by the deuteromycete Papularia sphaerosperma, inhibits the growth of yeasts. It is a highly amphophilic substance containing residues of glucose, galactose and two long-chain unsaturated fatty acids. It does not cause the release of potassium ions from yeast cells and therefore differs in its mode of action from the polyene antibiotics. Papulacandin B, at concentrations slightly below the minimal inhibitory concentration, partially but selectively inhibited the incorporation of glucose into cells of Saccharomyces cerevisiae and Candida albicans. A much clearer effect was observed on spheroplasts, obtained by digestion of the yeast cell wall with snail digestive enzyme. Incubation of spheroplasts in a minimal medium stabilised by sorbitol led to the incorporation of glucose into alkali-insoluble glucan, mannan and a fraction containing mainly alkali-soluble 1,3-glucan together with some glycogen. Papulacandin B inhibited the synthesis of the alkali-insoluble fraction, while causing a slight stimulation of glucose incorporation into the other two polysaccharide fractions. The 50 % inhibitory concentrations of papulacandin B for glucan synthesis in S. cerevisiae spheroplasts and C. albicans spheroplasts were respectively 0.16 pg/ml and 0.03 pg/ml. C. albicans cells were irradiated with ultraviolet light and selected for maximum resistance to papulacandin B. The 50 % inhibitory concentration for glucan synthesis in spheroplasts prepared from this mutant was 2.5 pg/ml. Echinocandin B, a polypeptide antibiotic containing a long-chain fatty acid, also inhibited the synthesis of glucan in spheroplasts. It is concluded that papulacandin B and probably also echinocandin B inhibit glucan synthesis during cell-wall synthesis, and thus cause lysis of cells by osmotic rupture.

Treatment of Pneumocystis carinii pneumonia with 1,3-beta-glucan synthesis inhibitors.

“…Both inhibited glucan synthesis (Fig. 4) as has been reported for related echinocandins and papulacandins (25)(26)(27) and had IC50 values of approximately 0.4 AM. Attempts to inhibit the formation of trichloroacetic acid-precipitable glucans produced by P. carinii membranes using these com- The total number of cysts per animal lung is expressed as the logarithm of the mean and the logarithm of the standard error of the geometric mean.…”

Compounds active against cell walls of medically important fungi

“…The mannan component is primarily composed of (1,6)-linked residues with (1,2) side chains, while the beta-D-galactofuranosyl units are (1,6) linked to the mannan core (11).…”

“…6,1993 on them to deduce the positions on the molecule most critical for activity. The carbamoyl polyoxamic acid moiety of polyoxin was thought to form a hydrogen bond with the chitin synthetase enzyme, with the amino group at C-2" the most critical for binding to the enzyme.…”

“…While the latter finding implies that this polymer is less critical for maintenance of the structural integrity of the hyphal wall, other evidence suggests that alpha-(1,3)-glucan, together with melanin, serves VOL. 6,1993 on April 6, 2019 by guest http://cmr.asm.org/ Downloaded from to protect hyphae from the action of hydrolytic enzymes, i.e., chitinase and beta-glucanase (191). In the case of the glucan, the latter property would presumably be a consequence of the physical barrier formed by this polymer in covering the inner layers of chitin and beta-(1,3)-glucan.…”

Glycoprotein molecules in the walls of Schizosaccharomyces pombe wild-type cells and a morphologically altered mutant resistant to papulacandin B

“…C. Ribas and co-workers (personal communication) have isolated a collection of S . pombe mutants resistant to papulacandin B, an inhibitor of glucan synthesis (Baguley et al, 1979;D u r h et al, 1984). One of these mutants, sphl (spherical shape), exhibits gross morphological alterations, and contains less galactomannan than the parent strain.…”