Adherence and receptor relationships of Candida albicans.

Candida albicans, like many fungi, exhibits morphological plasticity, a property which may be related to its biological capacity as an opportunistic pathogen of humans. Morphogenesis and alterations in cell shape require integration of many cellular functions and occur in response to environmental signals, most notably pH and temperature in the case of C. albicans. In the course of our studies of differential gene expression associated with dimorphism of C. albicans, we have isolated a gene, designated PHR1, which is regulated in response to the pH of the culture medium. PHR1 expression was repressed at pH values below 5.5 and induced at more alkaline pH. The predicted amino acid sequence of the PHR1 protein was 56% identical to that of the Saccharomyces cerevisiae Ggp1/Gas1 protein, a highly glycosylated cell surface protein attached to the membrane via glycosylphosphatidylinositol. A homozygous null mutant of PHR1 was constructed and found to exhibit a pH-conditional morphological defect. At alkaline pH, the mutant, unlike the parental type, was unable to conduct apical growth of either yeast or hyphal growth forms. This morphological aberration was not associated with defective cytoskeletal polarization or secretion. The results suggest that PHR1 defines a novel function required for apical cell growth and morphogenesis.

PHR1, a pH-regulated gene of Candida albicans, is required for morphogenesis.

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.

Compounds active against cell walls of medically important fungi.

Despite the many advances made during the last decade in various aspects of fungal biochemistry, there have been very few volumes devoted to the sub ject in recent years. This lack is all the more surprising in view of the increas ing use of fungi in gene manipulation studies and in biotechnological ap plications, and of the current interest in the biorational discovery of novel agents for the control of fungal pathogens of plants and humans. We hope that this book goes some way to rectifying this situation by providing an up to-date account of selected developments in two important areas, namely cell walls and membranes. Topics included in the book concern both yeasts and filamentous fungi. Although the main emphasis is on biogenesis, functional aspects are also discussed, e.g. the role of glycoproteins in recognition of sterols in mem branes and of calcium in regulation. Several contributions describe in terference with the 'normal' biochemistry of cell walls and membranes with a view to increasing fundamental knowledge, but also highly relevant to the design of new fungicides and antimycotics. The steadily increasing impact of molecular biology on the study of fungal biochemistry is highlighted throughout."

Biochemistry of Cell Walls and Membranes in Fungi

https://www.cell.com/trends/microbiology/pdf/S0966-842X(00)88890-3.pdf

The fungal cell wall as a drug target

Summary: Yeasts and mycelia of the pathogen Candida albicans grown in the presence of polyoxin D, a competitive inhibitor of chitin synthase, formed chains of swollen bulbous cells as observed by fluorescence microscopy. Wheat germ agglutinin (WGA) complexed to colloidal gold (Au) was used as a specific label at the ultrastructural level to visualize chitin in walls of control and polyoxin-treated cells. In control cells, Au-WGA labelling was preferentially localized in the innermost wall layers and was predominant at bud scars and septa. After 4·5 h in 4 mM-polyoxin D, budding in yeasts and lateral wall growth in mycelia continued, but primary septa failed to form and no Au-WGA labelling was detected in the walls. These results demonstrated that the morphological alterations caused by polyoxin D were due to the absence of chitin, a wall component important for formation of primary septa and for maintenance of structural integrity during morphogenesis.

L. L. Hilenski

Papers

Polyoxin D inhibits colloidal gold-wheat germ agglutinin labelling of chitin in dimorphic forms of Candida albicans.