Kenneth DenBleyker
Bristol-Myers Squibb
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Featured researches published by Kenneth DenBleyker.
Antimicrobial Agents and Chemotherapy | 2004
Michael J. Pucci; Joanne J. Bronson; John F. Barrett; Kenneth DenBleyker; Linda F. Discotto; Joan Fung-Tomc; Yasutsugu Ueda
ABSTRACT Nocathiacins are cyclic thiazolyl peptides with inhibitory activity against gram-positive bacteria. BMS-249524 (nocathiacin I), identified from screening a library of compounds against a multiply antibiotic-resistant Enterococcus faecium strain, was used as a lead chemotype to obtain additional structurally related compounds. The MIC assay results of BMS-249524 and two more water-soluble derivatives, BMS-411886 and BMS-461996, revealed potent in vitro activities against a variety of gram-positive pathogens including methicillin-resistant Staphylococcus aureus, penicillin-resistant Streptococcus pneumoniae, vancomycin intermediate-resistant S. aureus, vancomycin-resistant enterococci, Mycobacterium tuberculosis and Mycobacterium avium. Analysis of killing kinetics revealed that these compounds are bactericidal for S. aureus with at least a 3-log10 reduction of bacterial growth within 6 h of exposure to four times the MICs. Nocathiacin-resistant mutants were characterized by DNA sequence analyses. The mutations mapped to the rplK gene encoding the L11 ribosomal protein in the 50S subunit in a region previously shown to be involved in the binding of related thiazolyl peptide antibiotics. These compounds demonstrated potential for further development as a new class of antibacterial agents with activity against key antibiotic-resistant gram-positive bacterial pathogens.
Bioorganic & Medicinal Chemistry Letters | 2003
Joanne J. Bronson; Kenneth DenBleyker; Paul Falk; Robert A. Mate; Hsu-Tso Ho; Michael J. Pucci; Lawrence B. Snyder
A series of imidazolinone analogues was synthesized and shown to possess potent MurB inhibitory as well as good antibacterial activity.
Antimicrobial Agents and Chemotherapy | 2001
Linda F. Discotto; Laura Lawrence; Kenneth DenBleyker; John F. Barrett
ABSTRACT BMS-284756, a novel des-fluoro(6)-quinolone, was used to select for in vitro mutants of Staphylococcus aureusISP794. Step mutants were obtained, and the quinolone resistance-determining regions of four target genes, gyrA, gyrB, grlA, and grlB, were sequenced. The data suggest that DNA gyrase is the primary target for BMS-284756 in S. aureus.
Antimicrobial Agents and Chemotherapy | 2001
Sandra L. Hartman‐Neumann; Kenneth DenBleyker; Lenore Pelosi; Laura Lawrence; John F. Barrett; Thomas J. Dougherty
ABSTRACT Existing quinolones are known to target the type II topoisomerases in bacteria. In order to determine which of these targets are of key importance in Streptococcus pneumoniae treated with BMS-284756 (T-3811ME), a novel des-F(6) quinolone, resistant mutants were selected in several steps of increasing resistance by plating pneumococci on a series of blood agar plates containing serial twofold-increasing concentrations of drug. After incubation, colonies that arose were selected and passaged twice on antibiotic-containing media at the selection level. Mutants generally showed increases in resistance of four- to eightfold over the prior level of susceptibility. Mutants in the next-higher level of resistance were selected from the previous round of resistant mutants. Subsequently, chromosomal DNA was prepared from parental (R6) pneumococci and from at least three clones from each of four levels of increasing antibiotic resistance. Using PCR primers, 500- to 700-bp amplicons surrounding the quinolone resistance determining regions (QRDR) ofgyrA, gyrB, parC, andparE genes were prepared from each strain. Internal primers were used to sequence both DNA strands in the regions of approximately 400 bp centered on the QRDR. Mutations identified with increasing levels of resistance included changes in GyrA at Ser-81 and Glu-85 and changes in ParC at Ser-79 and Asp-83. Changes in GyrB and ParE were not observed at the levels of resistance obtained in this selection. The resistance to comparator quinolones (levofloxacin, ciprofloxacin, and moxifloxacin) also increased in four- to eightfold steps with these mutations. The intrinsically greater level of antibacterial activity and thus lower MICs of BMS-284756 observed at all resistance levels in this study may translate to coverage of these resistant pneumococcal strains in the clinic.
Antimicrobial Agents and Chemotherapy | 2001
Ping Wu; Laura Lawrence; Kenneth DenBleyker; John F. Barrett
ABSTRACT BMS-284756 (T-3811ME), a novel des-F(6) quinolone, was tested in the supercoiling inhibition and cleavable complex assays against Escherichia coli DNA gyrase, a target of quinolones. The results suggest that BMS-284756 has the same mechanism of action against DNA gyrase as other quinolones and a similar level of potency.
Bioorganic & Medicinal Chemistry Letters | 2005
Stan D’Andrea; Zhizhen Barbara Zheng; Kenneth DenBleyker; Joan Fung-Tomc; Hyekyung Yang; Junius M. Clark; Dennis Taylor; Joanne J. Bronson
Bioorganic & Medicinal Chemistry Letters | 2004
Lawrence B. Snyder; Zhaoxing Meng; Robert A. Mate; Stanley V. D’Andrea; Anne Marinier; Claude A. Quesnelle; Patrice Gill; Kenneth DenBleyker; Joan Fung-Tomc; MaryBeth Frosco; Alain Martel; John F. Barrett; Joanne J. Bronson
Journal of Antimicrobial Chemotherapy | 2001
Laura Lawrence; Ping Wu; Li Fan; Kristine Gouveia; Amy Card; Margaret Casperson; Kenneth DenBleyker; John F. Barrett
European Journal of Medicinal Chemistry | 2007
Dane M. Springer; Amy Bunker; Bing-Yu Luh; Margaret E. Sorenson; Jason Goodrich; Joanne J. Bronson; Kenneth DenBleyker; Thomas J. Dougherty; Joan Fung-Tomc
Journal of Clinical Microbiology | 1991
Joan Fung-Tomc; E Huczko; Elizabeth Gradelski; Kenneth DenBleyker; D P Bonner; R E Kessler