Jean A. Marrinan
Merck & Co.
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Featured researches published by Jean A. Marrinan.
Antimicrobial Agents and Chemotherapy | 1994
Myra B. Kurtz; I B Heath; Jean A. Marrinan; S Dreikorn; Janet C. Onishi; Cameron M. Douglas
The lipopeptide antifungal agents, echinocandins, papulacandins, and pneumocandins, kill Candida albicans by inhibiting glucan synthesis. For this fungus, there is a good correlation of in vitro enzyme inhibition with in vitro assays of MICs. Semisynthetic lipopeptides such as cilofungin, LY303366, L-693,989, and L-733,560 have activity in vivo against Aspergillus infections but appear to be inactive in broth dilution in vitro tests (MICs, > 128 micrograms/ml). To understand how compounds which lack activity in vitro can have good in vivo activity, we monitored the effect of pneumocandins on the morphology of Aspergillus fumigatus and A, flavus strains by light microscopy and electron microscopy and related the changes in growth to inhibition of glucan synthesis. Pneumocandin B0 caused profound changes in hyphal growth; light micrographs showed abnormally swollen germ tubes, highly branched hyphal tips, and many cells with distended balloon shapes. Aspergillus electron micrographs confirmed that lipopeptides produce changes in cell walls; drug-treated germlings showed very stubby growth with thick walls and a conspicuous dark outer layer which was much thicker in the subapical regions. The rest of the hyphal tip ultrastructure was unaffected by the drug, indicating considerable specificity for the primary target. The drug-induced growth alteration produced very compact clumps in broth dilution wells, making it possible to score the morphological effect macroscopically. The morphological changes could be assayed quantitatively by using conventional broth microdilution susceptibility assay conditions. We defined the endpoint as the lowest concentration required to produce the morphological effect and called it the minimum effective concentration to distinguish it from the no-growth endpoints used in MIC determinations. The minimum effective concentration assay was related to inhibition of glucan synthase activity in vitro and may provide a starting point for development of susceptibility testing methods for lipopeptides. Images
Antimicrobial Agents and Chemotherapy | 1994
Myra B. Kurtz; Cameron M. Douglas; Jean A. Marrinan; K Nollstadt; Janet C. Onishi; S Dreikorn; J Milligan; S Mandala; J Thompson; James M. Balkovec
The pneumocandins are natural lipopeptide products of the echinocandin class which inhibit the synthesis of 1,3-beta-D-glucan in susceptible fungi. The lack of a corresponding pathway in mammalian hosts makes this mode of action an attractive one for treating systemic infections. Substitution by an aminoethyl ether at the hemiaminal and dehydration and reduction of the glutamine of pneumocandin B0 produced a semisynthetic compound (L-733,560) with intrinsic water solubility, significantly increased potency, and a broader antifungal spectrum. To evaluate the mechanism for the improved antifungal efficacy, we determined that L-733,560 was a more potent inhibitor of glucan synthase activity in vitro, did not affect the other membrane-bound enzymes tested, conferred susceptibility to lysis in the absence of osmotic support, and did not disrupt currents in liposomal bilayers or 86Rb+ fluxes from liposomes. In Aspergillus species L-733,560 also produced the same morphological alterations as pneumocandin B0. A stereoisomer of L-733,560 with poor antifungal activity was a weak inhibitor of glucan synthase. All of these results support the notion that the enhanced antifungal activity of L-733,560 is achieved by superior inhibition of glucan synthesis and not by nonspecific membrane effects or a second mode of action. Images
Antimicrobial Agents and Chemotherapy | 1995
Myra B. Kurtz; E M Bernard; F F Edwards; Jean A. Marrinan; J Dropinski; Cameron M. Douglas; D Armstrong
The pneumocandins are semisynthetic analogs of echinocandin-like compounds that have shown efficacy in animal models of systemic candidiasis, disseminated aspergillosis, and pneumocystis pneumonia. However, the most common form of Aspergillus infection in susceptible patients is pulmonary aspergillosis, which was not directly tested in the mouse models used in the past. We have evaluated three pneumocandins, L-693,989, L-731,373, and L-733,560, in a rat model of pulmonary aspergillosis. Male Sprague-Dawley rats were treated for 2 weeks with cortisone and tetracycline and fed a low-protein diet before being inoculated via the trachea with 10(6) conidia of Aspergillus fumigatus H11-20. In the absence of drug treatment, the animals developed a progressive, rapidly fatal bronchopneumonia. All three pneumocandins at doses of 5 mg/kg (intraperitoneally [i.p.] every 12 h [q12h]) were effective in delaying mortality in this model. Survival at day 7 postinfection was 20% among controls (n = 10 for all groups), while it was 60, 80, and 90% in groups that were treated with L-693,989, L-731,373, and L-733,560, respectively. In another trial, survival at day 7 postinfection was 25% among controls (n = 8 for all groups); it was 87.5% in a group treated with amphotericin B (0.5 mg/kg i.p. q12h) and was 100% in a group treated with L-733,560 (0.625 mg/kg i.p. q12h). In a separate trial, aerosol L-693,989 administered 2 h before infection (5 mg/kg) delayed mortality. Eight of the 10 animals treated with aerosol L-693,989 survived for 7 days, whereas only 2 of 10 control animals survived. We conclude that the pneumocandins we tested were highly effective in an animal model of pulmonary aspergillosis.
Bioorganic & Medicinal Chemistry Letters | 1995
Robert A. Zambias; Catherine James; Milton L. Hammond; George K. Abruzzo; Kenneth F. Bartizal; Karl H. Nollstadt; Cameron M. Douglas; Jean A. Marrinan; James M. Balkovec
Abstract Selective methanolysis or dehydration followed by reduction of the 3-hydroxyglutamine residue of pneumocandin B0 (1) or its dideoxy analog 5 (L-692,289) gave the methyl 3-hydroxyglutamate and 3-hydroxyornithine analogs 6 and 9, respectively. Further derivatization of these analogs allowed a study of the SAR at this position. In general, carboxylic acid-containing derivatives were poorer antifungal agents than neutral derivatives while amine-bearing analogs displayed the greatest potency.
Bioorganic & Medicinal Chemistry Letters | 1997
Robert A. Zambias; Catherine James; George K. Abruzzo; Kenneth F. Bartizal; Richard Hajdu; Randy Thompson; Karl H. Nollstadt; Jean A. Marrinan; James M. Balkovec
Abstract Amine conjugates of the semi-synthetic 1,3-β-(D)-glucan synthesis inhibitors L-731,373 (3) and L-733,560 (4) were prepared and evaluated for in vitro and in vivo antifungal activity. Tricationic analogs were more potent than the dicationic which were more potent than the monocationic. The L-ornithine conjugate of 4 possessed excellent pharmacokinetic parameters but lacked sufficient antifungal spectrum for development.
Antimicrobial Agents and Chemotherapy | 1997
Cameron M. Douglas; J A D'Ippolito; G J Shei; Maria S. Meinz; Janet C. Onishi; Jean A. Marrinan; W Li; George K. Abruzzo; Amy M. Flattery; Kenneth F. Bartizal; A Mitchell; Myra B. Kurtz
Journal of Bacteriology | 1994
Cameron M. Douglas; Jean A. Marrinan; W Li; Myra B. Kurtz
Journal of Medicinal Chemistry | 1994
F. Aileen Bouffard; Robert A. Zambias; James F. Dropinski; James M. Balkovec; Milton L. Hammond; George K. Abruzzo; Kenneth F. Bartizal; Jean A. Marrinan; Myra B. Kurtz
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
Archive | 1994
Cameron M. Douglas; Joseph Clemas; Gary Chrebet; Mohammed El-Sherbeini; Forrest Foor; Jennifer Nielsen Kahn; Rosemarie Kelly; Jean A. Marrinan; Nancy R. Morin; Janet C. Onishi; Stephen A. Parent; Naasa M. Ramadan; Gan-Ju Shei; Elizabeth Register