Rosemary A. Thornton
Merck & Co.
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Featured researches published by Rosemary A. Thornton.
Journal of Biological Chemistry | 1997
Suzanne M. Mandala; Rosemary A. Thornton; Mark Rosenbach; James A. Milligan; Margarita Garcia-Calvo; Herbert G. Bull; Myra B. Kurtz
In the course of screening for antifungal agents we have discovered a novel compound isolated from an endophytic fungus that inhibits fungal sphingolipid synthesis. Khafrefungin, which is composed of aldonic acid linked via an ester to a C22 modified alkyl chain, has fungicidal activity against Candida albicans,Cryptococcus neoformans, and Saccharomyces cerevisiae. Sphingolipid synthesis is inhibited in these organisms at the step in which phosphoinositol is transferred to ceramide, resulting in accumulation of ceramide and loss of all of the complex sphingolipids. In vitro, khafrefungin inhibits the inositol phosphoceramide synthase of C. albicans with an IC50 of 0.6 nm. Khafrefungin does not inhibit the synthesis of mammalian sphingolipids thus making this the first reported compound that is specific for the fungal pathway.
Journal of Biological Chemistry | 1998
Suzanne M. Mandala; Rosemary A. Thornton; James A. Milligan; Mark Rosenbach; Margarita Garcia-Calvo; Herbert G. Bull; Guy H. Harris; George K. Abruzzo; Amy M. Flattery; Charles Gill; Kenneth F. Bartizal; Sarah Dreikorn; Myra B. Kurtz
Rustmicin is a 14-membered macrolide previously identified as an inhibitor of plant pathogenic fungi by a mechanism that was not defined. We discovered that rustmicin inhibits inositol phosphoceramide synthase, resulting in the accumulation of ceramide and the loss of all of the complex sphingolipids. Rustmicin has potent fungicidal activity against clinically important human pathogens that is correlated with its sphingolipid inhibition. It is especially potent against Cryptococcus neoformans, where it inhibits growth and sphingolipid synthesis at concentrations <1 ng/ml and inhibits the enzyme with an IC50 of 70 pm. This inhibition of the membrane-bound enzyme is reversible; moreover, rustmicin is nearly equipotent against the solubilized enzyme. Rustmicin was efficacious in a mouse model for cryptococcosis, but it was less active than predicted from its in vitro potency against this pathogen. Stability and drug efflux were identified as two factors limiting rustmicin’s activity. In the presence of serum, rustmicin rapidly epimerizes at the C-2 position and is converted to a γ-lactone, a product that is devoid of activity. Rustmicin was also found to be a remarkably good substrate for the Saccharomyces cerevisiae multidrug efflux pump encoded by PDR5.
Science | 2002
Suzanne M. Mandala; Richard Hajdu; James D. Bergstrom; Elizabeth J. Quackenbush; Jenny Xie; James A. Milligan; Rosemary A. Thornton; Gan-Ju Shei; Deborah Card; CarolAnn Keohane; Mark Rosenbach; Jeffrey J. Hale; Christopher L. Lynch; Kathleen M. Rupprecht; William H. Parsons; Hugh Rosen
Proceedings of the National Academy of Sciences of the United States of America | 1998
Suzanne M. Mandala; Rosemary A. Thornton; Zhenxing Tu; Myra B. Kurtz; Joseph T. Nickels; James R. Broach; Ramil Menzeleev; Sarah Spiegel
Proceedings of the National Academy of Sciences of the United States of America | 2000
Suzanne M. Mandala; Rosemary A. Thornton; Ismael Galve-Roperh; Samantha Poulton; Courtney M. Peterson; Ana Olivera; James D. Bergstrom; Myra B. Kurtz; Sarah Spiegel
The Journal of Antibiotics | 1995
Suzanne M. Mandala; Rosemary A. Thornton; Beth R. Frommer; James E. Curotto; Walter Rozdilsky; Myra B. Kurtz; Robert A. Giacobbe; Gerald F. Bills; M. Angeles Cabello; Isabel Martin; Fernando Pelaez; Guy H. Harris
The Journal of Antibiotics | 1992
Wendy S. Horn; Jack L. Smith; Gerald F. Bills; Susan L. Raghoobar; Gregory L. Helms; Myra B. Kurtz; Jean A. Marrinan; Beth R. Frommer; Rosemary A. Thornton; Suzanne M. Mandala
The Journal of Antibiotics | 1997
Suzanne M. Mandala; Rosemary A. Thornton; Beth R. Frommer; Sarah Dreikorn; Myra B. Kurtz
The Journal of Antibiotics | 1994
Suzanne M. Mandala; Beth R. Frommer; Rosemary A. Thornton; Mrya B. Kurtz; Noel M. Young; M. Angeles Cabello; Olga Genilloud; Jerrold M. Liesch; Jack L. Smith; Wendy S. Horn
Bioorganic & Medicinal Chemistry | 2004
Jeffrey J. Hale; Lin Yan; William E. Neway; Richard Hajdu; James D. Bergstrom; James A. Milligan; Gan-Ju Shei; Gary Chrebet; Rosemary A. Thornton; Deborah Card; Mark Rosenbach; HughRosen; Suzanne M. Mandala