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33. Amidino benzimidazole inhibitors of bacterial two-component systems

Author

Weidner-Wells, Michele A., primary, Ohemeng, Kwasi A., additional, Nguyen, Van N., additional, Fraga-Spano, Stephanie, additional, Macielag, Mark J., additional, Werblood, Harvey M., additional, Foleno, Barbara D., additional, Webb, Glenda C., additional, Barrett, John F., additional, and Hlasta, Dennis J., additional

Published
2001
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37. Novel inhibitors of bacterial two-component systems with gram positive antibacterial activity: Pharmacophore identification based on the screening hit closantel

Author

Hlasta, Dennis J., primary, Demers, James P., additional, Foleno, Barbara D., additional, Fraga-Spano, Stephanie A., additional, Guan, Jihua, additional, Hilliard, Jamese J., additional, Macielag, Mark J., additional, Ohemeng, Kwasi A., additional, Sheppard, Cheryl M., additional, Sui, Zhihua, additional, Webb, Glenda C., additional, Weidner-Wells, Michele A., additional, Werblood, Harvey, additional, and Barrett, John F., additional

Published
1998
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38. Substituted Salicylanilides as Inhibitors of Two-Component Regulatory Systems in Bacteria

Author

Macielag, Mark J., primary, Demers, James P., additional, Fraga-Spano, Stephanie A., additional, Hlasta, Dennis J., additional, Johnson, Sigmond G., additional, Kanojia, Ramesh M., additional, Russell, Ronald K., additional, Sui, Zhihua, additional, Weidner-Wells, Michele A., additional, Werblood, Harvey, additional, Foleno, Barbara D., additional, Goldschmidt, Raul M., additional, Loeloff, Michael J., additional, Webb, Glenda C., additional, and Barrett, John F., additional

Published
1998
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45. In VitroAntibacterial Activities of JNJ-Q2, a New Broad-Spectrum Fluoroquinolone

Author

Morrow, Brian J., He, Wenping, Amsler, Karen M., Foleno, Barbara D., Macielag, Mark J., Lynch, A. Simon, and Bush, Karen

Abstract

ABSTRACTJNJ-Q2, a novel fluorinated 4-quinolone, was evaluated for its antibacterial potency by broth and agar microdilution MIC methods in studies focused on skin and respiratory tract pathogens, including strains exhibiting contemporary fluoroquinolone resistance phenotypes. Against a set of 118 recent clinical isolates of Streptococcus pneumoniae, including fluoroquinolone-resistant variants bearing multiple DNA topoisomerase target mutations, an MIC90value for JNJ-Q2 of 0.12 μg/ml was determined, indicating that it was 32-fold more potent than moxifloxacin. Against a collection of 345 recently collected methicillin-resistant Staphylococcus aureus(MRSA) isolates, including 256 ciprofloxacin-resistant strains, the JNJ-Q2 MIC90value was 0.25 μg/ml, similarly indicating that it was 32-fold more potent than moxifloxacin. The activities of JNJ-Q2 against Gram-negative pathogens were generally comparable to those of moxifloxacin. In further studies, JNJ-Q2 exhibited bactericidal activities at 2× and 4× MIC levels against clinical isolates of S. pneumoniaeand MRSA with various fluoroquinolone susceptibilities, and its activities were enhanced over those of moxifloxacin. In these studies, the activity exhibited against strains bearing gyrA, parC, or gyrAplus parCmutations was indicative of the relatively balanced (equipotent) activity of JNJ-Q2 against the DNA topoisomerase target enzymes. Finally, determination of the relative rates or frequencies of the spontaneous development of resistance to JNJ-Q2 at 2× and 4× MICs in S. pneumoniae, MRSA, and Escherichia coliwere indicative of a lower potential for resistance development than that for current fluoroquinolones. In conclusion, JNJ-Q2 exhibits a range of antibacterial activities in vitrothat is supportive of its further evaluation as a potential new agent for the treatment of skin and respiratory tract infections.

Published
2010
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46. Identification of a Dithiazoline Inhibitor of Escherichia colil,d-Carboxypeptidase A

Author

Baum, Ellen Z., Crespo-Carbone, Steven M., Foleno, Barbara, Peng, Sean, Hilliard, Jamese J., Abbanat, Darren, Goldschmidt, Raul, and Bush, Karen

Abstract

ABSTRACTThe enzyme l,d-carboxypeptidase A is involved in the recycling of bacterial peptidoglycan and is essential in Escherichia coliduring stationary phase. By high-throughput screening, we have identified a dithiazoline inhibitor of the enzyme with a 50% inhibitory concentration of 3 μM. The inhibitor appeared to cause lysis of E. coliduring stationary phase, behavior that is similar to a previously described deletion mutant of l,d-carboxypeptidase A (M. F. Templin, A. Ursinus, and J.-V. Holtje, EMBO J. 18:4108-4117, 1999). As much as a one-log drop in CFU in stationary phase was observed upon treatment of E. coliwith the inhibitor, and the amount of intracellular tetrapeptide substrate increased by approximately 33%, consistent with inhibition of the enzyme within bacterial cells. Stationary-phase targets such as l,d-carboxypeptidase A are largely underrepresented as targets of the antibiotic armamentarium but provide potential opportunities to interfere with bacterial growth and persistence.

Published
2005
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47. Effects of inoculum and beta-lactamase activity in AmpC- and extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli and Klebsiella pneumoniae clinical isolates tested by using NCCLS ESBL methodology.

Author

Queenan, Anne Marie, Foleno, Barbara, Gownley, Colleen, Wira, Ellyn, and Bush, Karen

Abstract

Escherichia coli and Klebsiella pneumoniae isolates with extended-spectrum beta-lactamases (ESBLs) or AmpC cephalosporinases generally respond as predicted to NCCLS tests for ESBL production. However, inoculum size may affect MICs. The effect of inoculum level in clinical isolates expressing beta-lactamases were studied at inocula within 0.5 log unit of the standard inoculum, using broth microdilution methodology with ceftazidime, cefotaxime, cefepime, cefpodoxime, and aztreonam. Strains with TEM-1 or no beta-lactamases gave consistent MIC results with inocula of 10(5) and 10(6) CFU/ml. When the bacteria were screened for ESBL production and the lower inoculum was used, several strains with ESBLs, including CTX-M-10, TEM-3, TEM-10, TEM-12, TEM-6, SHV-18, and K1, gave false-negative results for one or more antimicrobial agents (MICs below the NCCLS screening concentration for detecting suspected ESBLs). When the higher inoculum was used, MICs of at least one antimicrobial agent increased at least fourfold in strains producing TEM-3, TEM-10, TEM-28, TEM-43, SHV-5, SHV-18, and K1. All antimicrobial agents showed an inoculum effect with at least one ESBL producer. Confirmatory clavulanate effects were seen for both inocula for all ESBL-producing strains with all antimicrobial agents tested, except for the CTX-M-10-producing E. coli with ceftazidime and the SHV-18-producing K. pneumoniae with cefotaxime. In kinetic studies, cefpodoxime and cefepime were hydrolyzed by ESBLs in a manner similar to that of cefotaxime. When total beta-lactamase activity and hydrolysis parameters were evaluated, however, no single factor was predictive of inoculum effects. These results indicate that the NCCLS screening and confirmation tests are generally predictive of ESBL production, but false-negative results can arise when a lower inoculum is used in testing.

Published
2004

48. Effects of Inoculum and ß-Lactamase Activity in AmpC- and Extended-Spectrum ß-Lactamase (ESBL)-Producing Escherichia coliand Klebsiella pneumoniaeClinical Isolates Tested by Using NCCLS ESBL Methodology

Author

Queenan, Anne Marie, Foleno, Barbara, Gownley, Colleen, Wira, Ellyn, and Bush, Karen

Abstract

ABSTRACTEscherichia coliand Klebsiella pneumoniaeisolates with extended-spectrum ß-lactamases (ESBLs) or AmpC cephalosporinases generally respond as predicted to NCCLS tests for ESBL production. However, inoculum size may affect MICs. The effect of inoculum level in clinical isolates expressing ß-lactamases were studied at inocula within 0.5 log unit of the standard inoculum, using broth microdilution methodology with ceftazidime, cefotaxime, cefepime, cefpodoxime, and aztreonam. Strains with TEM-1 or no ß-lactamases gave consistent MIC results with inocula of 105and 106CFU/ml. When the bacteria were screened for ESBL production and the lower inoculum was used, several strains with ESBLs, including CTX-M-10, TEM-3, TEM-10, TEM-12, TEM-6, SHV-18, and K1, gave false-negative results for one or more antimicrobial agents (MICs below the NCCLS screening concentration for detecting suspected ESBLs). When the higher inoculum was used, MICs of at least one antimicrobial agent increased at least fourfold in strains producing TEM-3, TEM-10, TEM-28, TEM-43, SHV-5, SHV-18, and K1. All antimicrobial agents showed an inoculum effect with at least one ESBL producer. Confirmatory clavulanate effects were seen for both inocula for all ESBL-producing strains with all antimicrobial agents tested, except for the CTX-M-10-producing E. coliwith ceftazidime and the SHV-18-producing K. pneumoniaewith cefotaxime. In kinetic studies, cefpodoxime and cefepime were hydrolyzed by ESBLs in a manner similar to that of cefotaxime. When total ß-lactamase activity and hydrolysis parameters were evaluated, however, no single factor was predictive of inoculum effects. These results indicate that the NCCLS screening and confirmation tests are generally predictive of ESBL production, but false-negative results can arise when a lower inoculum is used in testing.

Published
2004
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49. Identification and Characterization of New Inhibitors of the Escherichia coliMurA Enzyme

Author

Baum, Ellen Z., Montenegro, Deborah A., Licata, Lisa, Turchi, Ignatius, Webb, Glenda C., Foleno, Barbara D., and Bush, Karen

Abstract

ABSTRACTThe bacterial enzyme MurA catalyzes the transfer of enolpyruvate from phosphoenolpyruvate (PEP) to uridine diphospho-N-acetylglucosamine (UNAG), which is the first committed step of bacterial cell wall biosynthesis. From high-throughput screening of a chemical library, three novel inhibitors of the Escherichia coliMurA enzyme were identified: the cyclic disulfide RWJ-3981, the purine analog RWJ-140998, and the pyrazolopyrimidine RWJ-110192. When MurA was preincubated with inhibitor, followed by addition of UNAG and PEP, the 50% inhibitory concentrations (IC50s) were 0.2 to 0.9 μM, compared to 8.8 μM for the known MurA inhibitor, fosfomycin. The three compounds exhibited MICs of 4 to 32 μg/ml against Staphylococcus aureus; however, the inhibition of DNA, RNA, and protein synthesis in addition to peptidoglycan synthesis by all three inhibitors indicated that antibacterial activity was not due specifically to MurA inhibition. The presence of UNAG during the MurA and inhibitor preincubation lowered the IC50at least fivefold, suggesting that, like fosfomycin, the three compounds may interact with the enzyme in a specific fashion that is enhanced by UNAG. Ultrafiltration and mass spectrometry experiments suggested that the compounds were tightly, but not covalently, associated with MurA. Molecular modeling studies demonstrated that the compounds could fit into the site occupied by fosfomycin; exposure of MurA to each compound reduced the labeling of MurA by tritiated fosfomycin. Taken together, the evidence indicates that these inhibitors may bind noncovalently to the MurA enzyme, at or near the site where fosfomycin binds.

Published
2001
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