The increasing incidence of life-threatening fungal infections has driven the search for new, broad-spectrum fungicidal agents that can be used for treatment and prophylaxis in immunocompromised patients. Naturalproduct inhibitors of cell wall (

Pneumocystis carini pneumonia is a major cause of death in AIDS patients in the United States. The presently available treatments have limited use due to a high incidence of adverse reactions. Therefore, there is an urgent need for a safer method for treatment and prevention of this disease. Recent evidence has suggested that P. carinn is related to fungi and that the wall ofthe cyst form contains 1,3-13-glucan as a major constituent. Based on this, several proposed 1,3-f3-glucan synthesis inhibitors were evaluated for their ability to control P. carinu pneumonia in vivo. Compounds from two classes of 1,3-13-glucan synthesis inhibitors, the echinocandins and papulacandins, were found to be effective against P. carinii.Pneumocystis carinii pneumonia is the most prevalent opportunistic infection and a frequent cause of death in AIDS

Natural products provide an unparalleled source of chemical scaffolds with diverse biological activities and have profoundly impacted antimicrobial drug discovery. To further explore the full potential of their chemical diversity, we survey natural products for antifungal, target-specific inhibitors by using a chemical-genetic approach adapted to the human fungal pathogen Candida albicans and demonstrate that natural-product fermentation extracts can be mechanistically annotated according to heterozygote strain responses. Applying this approach, we report the discovery and characterization of a natural product, parnafungin, which we demonstrate, by both biochemical and genetic means, to inhibit poly(A) polymerase. Parnafungin displays potent and broad spectrum activity against diverse, clinically relevant fungal pathogens and reduces fungal burden in a murine model of disseminated candidiasis. Thus, mechanism-of-action determination of crude fermentation extracts by chemical-genetic profiling brings a powerful strategy to natural-product-based drug discovery.

The authors recently have shown that triplication of the alpha-synuclein gene (SNCA) can cause Parkinson disease (PD) and diffuse Lewy body disease within the same kindred. The authors assessed 101 familial PD probands, 325 sporadic PD cases, 65 patients with dementia with Lewy bodies, and 366 neurologically normal control subjects for SNCA multiplication. The authors did not identify any subjects with multiplication of SNCA and conclude this mutation is a rare cause of disease.

A new /M,3-D-glucan synthesis inhibitor, L-687,781 is produced by the cultivation of Dictyochaeta simplex ATCC20960. L-687,781 exhibits potent in vitro antifungal activity as well as anti-Pneumocystis activity in a rat model.