Abstract:
:The anilinouracils (AUs) such as 6-(3-ethyl-4-methylanilino)uracil (EMAU) are a novel class of gram-positive, selective, bactericidal antibacterials which inhibit pol IIIC, the gram-positive-specific replicative DNA polymerase. We have linked various fluoroquinolones (FQs) to the N-3 position of EMAU to generate a variety of AU-FQ "hybrids" offering the potential for targeting two distinct steps in DNA replication. In this study, the properties of a hybrid, "251D," were compared with those of representative AUs and FQs in a variety of in vitro assays, including pol IIIC and topoisomerase/gyrase enzyme assays, antibacterial, bactericidal, and mammalian cytotoxicity assays. Compound 251D potently inhibited pol IIIC and topoisomerase/gyrase, displayed gram-positive antibacterial potency at least 15 times that of the corresponding AU compound, and as expected, acted selectively on bacterial DNA synthesis. Compound 251D was active against a broad panel of antibiotic-resistant gram-positive pathogens as well as several gram-negative organisms and was also active against both AU- and FQ-resistant gram-positive organisms, demonstrating its capacity for attacking both of its potential targets in the bacterium. 251D also was bactericidal for gram-positive organisms and lacked toxicity in vitro. Although we obtained strains of Staphylococcus aureus resistant to the individual parent compounds, spontaneous resistance to 251D was not observed. We obtained 251D resistance in multiple-passage experiments, but resistance developed at a pace comparable to those for the parent compounds. This class of AU-FQ hybrids provides a promising new pharmacophore with an unusual dual mechanism of action and potent activity against antibiotic-sensitive and -resistant gram-positive pathogens.
journal_name
Antimicrob Agents Chemotherjournal_title
Antimicrobial agents and chemotherapyauthors
Butler MM,Lamarr WA,Foster KA,Barnes MH,Skow DJ,Lyden PT,Kustigian LM,Zhi C,Brown NC,Wright GE,Bowlin TLdoi
10.1128/AAC.01311-05subject
Has Abstractpub_date
2007-01-01 00:00:00pages
119-27issue
1eissn
0066-4804issn
1098-6596pii
AAC.01311-05journal_volume
51pub_type
杂志文章abstract::Most methicillin-resistant Staphylococcus aureus (MRSA) isolates identified among blood isolates collected in Denmark between 1957 and 1970 belonged to either phage group III or the closely related 83A complex and had a PSTM antibiotype (resistance to penicillin [P], streptomycin [S], tetracycline [T], and methicillin...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00521-06
更新日期:2006-10-01 00:00:00
abstract::We have isolated in vitro fluoroquinolone-resistant mutants of the Lyme disease agent, Borrelia burgdorferi. Mutations in parC, which encodes a subunit of topoisomerase IV, were associated with loss of susceptibility to sparfloxacin, moxifloxacin, and Bay-Y3118, but not ciprofloxacin. This is the first description of ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.49.10.4354-4357.2005
更新日期:2005-10-01 00:00:00
abstract::Hemicholinium 3, decamethonium, and decyltrimethylammonium previously have been demonstrated to be efficient inhibitors, with 50% inhibitory concentrations of 4 X 10(-6), 10(-6), and 7 X 10(-7) M, respectively. We show that lengthening of the alkyl chain of decyltrimethylammonium by successive additions of two carbon ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.29.5.814
更新日期:1986-05-01 00:00:00
abstract::Ceftolozane-tazobactam (C/T) is a novel cephalosporin with in vitro activity against Pseudomonas aeruginosa that is resistant to extended-spectrum penicillins and antipseudomonal cephalosporins. In order to assess the antimicrobial effect of C/T in treatment of Pseudomonas pneumonia, we investigated the pharmacokineti...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00344-19
更新日期:2019-08-23 00:00:00
abstract::The antibiotic susceptibilities of 62 strains of Salmonella enterica serovar Typhi and 37 strains of S. enterica serovar Paratyphi A were investigated with 18 antibiotics. Eighteen S. enterica serovar Typhi isolates and five S. enterica serovar Paratyphi A isolates were resistant to one or more antimicrobial agents, a...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.45.3.956-958.2001
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abstract::A pyridodiazepine amine inhibitor of Helicobacter pylori glutamate racemase (MurI) was characterized. The compound was selectively active against H. pylori, and growth suppression was shown to be mediated through the inhibition of MurI by several methods. In killing kinetics experiments, the compound showed concentrat...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.04410-14
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abstract::A Cedecea davisae isolate, which was intermediate or resistant to third-generation cephalosporins and carbapenems, was recovered from a urine sample. Susceptibility testing, isoelectric focusing, and analysis of outer membrane proteins showed that AmpC β-lactamase expression combined with porin deficiency accounted fo...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.03237-14
更新日期:2014-11-01 00:00:00
abstract::Two Klebsiella pneumoniae isolates of the same strain, identified in Poland, produced either TEM-47 or TEM-68, which differed by the Arg275Leu substitution. They harbored a few virulence factors, including an iron-chelating factor and capsule overproduction, suggesting that these factors were sufficient to enhance the...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.05079-11
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abstract::Aggregatibacter actinomycetemcomitans, a periodontopathogen, has been associated with several systemic diseases. Herein, we report the protective effect of human lactoferrin (hLF) during A. actinomycetemcomitans bacteremia in lactoferrin knockout (LFKO(-/-)) mice. The prophylactic, concurrent, and therapeutic intraven...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00020-13
更新日期:2014-01-01 00:00:00
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journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.35.4.622
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abstract::The susceptibility of 12 strains of Mobiluncus curtisii and 10 strains of M. mulieris to 23 antimicrobial agents and 15 other compounds was determined. All strains were susceptible to chloramphenicol, clindamycin, rifampin, tobramycin, vancomycin, virginiamycin, and all beta-lactam antibiotics tested, including imipen...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.31.2.249
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abstract::The therapeutic effect of intranasally administered enviroxime was tested against naturally occurring common colds. The double-blind evaluation was carried out in Tecumseh, Mich., during a period when rhinoviruses are usually the principal pathogen. Rhinovirus transmission followed the typical pattern during this peri...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 临床试验,杂志文章,随机对照试验
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abstract::GSK1322322 is a novel inhibitor of peptide deformylase (PDF) with good in vitro activity against bacteria associated with community-acquired pneumonia and skin infections. We have characterized the in vivo pharmacodynamics (PD) of GSK1322322 in immunocompetent animal models of infection with Streptococcus pneumoniae a...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.01842-15
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abstract::The pharmacokinetics of gentamicin in 34 febrile neutropenic patients (40 courses) were compared with those in 40 nonneutropenic patients receiving the drug. No pharmacokinetic differences were seen in half-life, volume of distribution (liter per kilogram; total and ideal body weight), or clearance (milliliter per min...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.33.11.1890
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journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.47.11.3653-3656.2003
更新日期:2003-11-01 00:00:00
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journal_title:Antimicrobial agents and chemotherapy
pub_type: 临床试验,杂志文章
doi:10.1128/aac.44.3.752-755.2000
更新日期:2000-03-01 00:00:00
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journal_title:Antimicrobial agents and chemotherapy
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journal_title:Antimicrobial agents and chemotherapy
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abstract::Primaquine is currently the only drug available for radical cure of Plasmodium vivax and P. ovale liver infection stages, but limited safety data exist for children <10 years of age. Detailed daily assessments of side effects in glucose-6-phosphate dehydrogenase (G6PD)-normal children treated with 14 days of primaquin...
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journal_title:Antimicrobial agents and chemotherapy
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journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
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journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
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更新日期:2007-06-01 00:00:00
abstract::Hepatitis C virus (HCV) NS3 protease inhibitors (PIs) are important components of novel HCV therapy regimens. Studies of PI resistance initially focused on genotype 1. Therefore, knowledge about the determinants of PI resistance for the highly prevalent genotypes 2 to 6 remains limited. Using Huh7.5 cell culture-infec...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
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更新日期:2016-05-23 00:00:00
abstract::Staphylococcal isolates were examined for possible macrolide-inducible resistance to telithromycin. All macrolide-resistant isolates demonstrated telithromycin D-shaped zones. This result did not discriminate between resistance due to an efflux mechanism (msrA) or a ribosomal target modification (ermA or ermC). Induci...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
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journal_title:Antimicrobial agents and chemotherapy
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abstract::The emergence of Neisseria gonorrhoeae isolates displaying resistance to antimicrobial agents is a major public health concern and a serious issue related to the occurrence of further untreatable gonorrhea infections. A retrospective analysis on 1,430 N. gonorrhoeae isolates, collected from 2003 through 2012, for anti...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
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journal_title:Antimicrobial agents and chemotherapy
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journal_title:Antimicrobial agents and chemotherapy
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doi:
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