Stewart Pearson
GlaxoSmithKline
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Featured researches published by Stewart Pearson.
Antimicrobial Agents and Chemotherapy | 2002
David J. Payne; William H. Miller; Valerie Berry; John Brosky; Walter J. Burgess; Emile Chen; Walter E. DeWolf; Andrew Fosberry; Rebecca Greenwood; Martha S. Head; Dirk A. Heerding; Cheryl A. Janson; Deborah Dee Jaworski; Paul M. Keller; Peter J. Manley; Terrance D. Moore; Kenneth A. Newlander; Stewart Pearson; Brian J. Polizzi; Xiayang Qiu; Stephen Rittenhouse; Courtney Slater-Radosti; Kevin L. Salyers; Mark A. Seefeld; Martin G. Smyth; Dennis T. Takata; Irene Nijole Uzinskas; Kalindi Vaidya; Nicola G. Wallis; Scott B. Winram
ABSTRACT Bacterial enoyl-acyl carrier protein (ACP) reductase (FabI) catalyzes the final step in each elongation cycle of bacterial fatty acid biosynthesis and is an attractive target for the development of new antibacterial agents. High-throughput screening of the Staphylococcus aureus FabI enzyme identified a novel, weak inhibitor with no detectable antibacterial activity against S. aureus. Iterative medicinal chemistry and X-ray crystal structure-based design led to the identification of compound 4 [(E)-N-methyl-N-(2-methyl-1H-indol-3-ylmethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylamide], which is 350-fold more potent than the original lead compound obtained by high-throughput screening in the FabI inhibition assay. Compound 4 has exquisite antistaphylococci activity, achieving MICs at which 90% of isolates are inhibited more than 500 times lower than those of nine currently available antibiotics against a panel of multidrug-resistant strains of S. aureus and Staphylococcus epidermidis. Furthermore, compound 4 exhibits excellent in vivo efficacy in an S. aureus infection model in rats. Biochemical and genetic approaches have confirmed that the mode of antibacterial action of compound 4 and related compounds is via inhibition of FabI. Compound 4 also exhibits weak FabK inhibitory activity, which may explain its antibacterial activity against Streptococcus pneumoniae and Enterococcus faecalis, which depend on FabK and both FabK and FabI, respectively, for their enoyl-ACP reductase function. These results show that compound 4 is representative of a new, totally synthetic series of antibacterial agents that has the potential to provide novel alternatives for the treatment of S. aureus infections that are resistant to our present armory of antibiotics.
Antimicrobial Agents and Chemotherapy | 2002
David J. Payne; Juan A. Hueso-Rodríguez; Helen F. Boyd; Nestor O. Concha; Cheryl A. Janson; Martin L. Gilpin; John H. Bateson; Christy Cheever; Nancy Niconovich; Stewart Pearson; Stephen Rittenhouse; David G. Tew; Emilio Diez; Paloma Perez; Jesús Ángel de la Fuente; Michael Rees; Alfonso Rivera-Sagredo
ABSTRACT This work describes the discovery and characterization of a novel series of tricyclic natural product-derived metallo-β-lactamase inhibitors. Natural product screening of the Bacillus cereus II enzyme identified an extract from a strain of Chaetomium funicola with inhibitory activity against metallo-β-lactamases. SB236050, SB238569, and SB236049 were successfully extracted and purified from this extract. The most active of these compounds was SB238569, which possessed Ki values of 79, 17, and 3.4 μM for the Bacillus cereus II, Pseudomonas aeruginosa IMP-1, and Bacteroides fragilis CfiA metallo-β-lactamases, respectively, yet none of the compounds exhibited any inhibitory activity against the Stenotrophomonas maltophilia L-1 metallo-β-lactamase (50% inhibitory concentration > 1,000 μM). The lack of activity against angiotensin-converting enzyme and serine β-lactamases demonstrated the selective nature of these compounds. The crystal structure of SB236050 complexed in the active site of CfiA has been obtained to a resolution of 2.5 Å. SB236050 exhibits key polar interactions with Lys184, Asn193, and His162 and a stacking interaction with the indole ring of Trp49 in the flap, which is in the closed conformation over the active site groove. SB236050 and SB238569 also demonstrate good antibacterial synergy with meropenem. Eight micrograms of SB236050 per ml gave rise to an eightfold drop in the MIC of meropenem for two clinical isolates of B. fragilis producing CfiA, making these strains sensitive to meropenem (MIC ≤ 4 μg/ml). Consequently, this series of metallo-β-lactamase inhibitors exhibit the most promising antibacterial synergy activity so far observed against organisms producing metallo-β-lactamases.
Biochemistry | 2000
Nestor O. Concha; Cheryl A. Janson; Pam Rowling; Stewart Pearson; Christy Cheever; Brian P. Clarke; Ceri Lewis; Moreno Galleni; Jean-Marie Frère; David J. Payne; John H. Bateson; Sherin S. Abdel-Meguid
Journal of Medicinal Chemistry | 2003
Mark A. Seefeld; William H. Miller; Kenneth A. Newlander; Walter J. Burgess; Walter E. DeWolf; Patricia A. Elkins; Martha S. Head; Dalia R. Jakas; Cheryl A. Janson; Paul M. Keller; Peter J. Manley; Terrance D. Moore; David J. Payne; Stewart Pearson; Brian J. Polizzi; Xiayang Qiu; Stephen Rittenhouse; Irene Nijole Uzinskas; Nicola G. Wallis; William F. Huffman
Journal of Medicinal Chemistry | 2002
William Henry Miller; Mark A. Seefeld; Kenneth A. Newlander; Irene N. Uzinskas; Walter J. Burgess; Dirk A. Heerding; Catherine C.K. Yuan; Martha S. Head; David J. Payne; Stephen Rittenhouse; Terrance D. Moore; Stewart Pearson; Valerie Berry; Walter E. DeWolf; Paul M. Keller; Brian J. Polizzi; Xiayang Qiu; Cheryl A. Janson; William F. Huffman
Fems Microbiology Letters | 1997
David J. Payne; John H. Bateson; Brian Charles Gasson; Teresa Khushi; David Proctor; Stewart Pearson; Robert C. Reid
Archive | 1997
David J. Payne; Peter Henry Milner; Stewart Pearson; John T. Lonsdale
Archive | 1997
John T. SmithKline Beecham Pharm. Lonsdale; Peter Henry Milner; David J. Payne; Stewart Pearson
Archive | 1999
David J. Payne; Peter Henry Milner; Stewart Pearson; John T. Lonsdale
Archive | 2000
Walter E. DeWolf; David J. Payne; Peter Henry Milner; Stewart Pearson; John T. Lonsdale