Abstract:
:Ofloxacin, a potent quinolone antibacterial agent, has a tricyclic ring structure with a methyl group attached to the asymmetric carbon at the C-3 position on the oxazine ring. The S isomer (DR-3355) of ofloxacin has antibacterial activity up to 2 orders of magnitude greater than that of the R isomer (DR-3354). This differential antibacterial activity was not due to different drug transport mechanisms of the two isomers but was found to be derived from the inhibitory activity against the target enzyme, DNA gyrase. Previous mechanistic studies have suggested that the bactericidal effect of the drug is mediated through the stabilization of a cleavable complex via a cooperative drug binding process to a partially denatured DNA pocket created by DNA gyrase. The drug binds to supercoiled DNA in a manner similar to that to which it binds to the enzyme-DNA complex. In the present studies, we first examined the binding of the two radiolabeled ofloxacin enantiomers to supercoiled pUC9 plasmid DNA. Surprisingly, the two enantiomers possessed similar apparent binding affinities and binding cooperatives. The major difference in binding between the two stereoisomers was the molar binding ratio: 4 for the more active S isomer versus 2 for the less active R isomer. We next examined the relative binding potencies of the stereoisomers to the DNA-DNA gyrase complex. The results of a competition assay showed that (S)-ofloxacin binds 12-fold better to the complex than (R)-ofloxacin. The binding potencies of the two enantiomers and two other quinolones correlated well with their respective concentrations causing 50% inhibition against DNA gyrase. The results are interpreted by a stacking model by using the concept of the cooperative drug-DNA binding mechanism, indicating that the potencies of quinolones cannot be determined solely by the DNA binding affinity and cooperativity but can also be determined by their capability in maximally saturating the binding site. The capability of the drug in saturating the binding pocket manifests itself in an increased efficacy at inhibiting the enzyme through a direct interaction between the drug and the enzyme. The results augment the previous suggestion that the binding pocket in the enzyme-DNA complex involves multiple receptor groups including not only DNA bases but also a gyrase subunit. The higher level of potency of (S)-ofloxacin is proposed to derive from the fact that a greater number of molecules are assembled in the pocket. This greater number of molecules optimizes the interaction between the drug and the enzyme, possibly through a contact between the C-7 substituent and the quinolone pocket on the B subunit of DNA gyrase.
journal_name
Antimicrob Agents Chemotherjournal_title
Antimicrobial agents and chemotherapyauthors
Morrissey I,Hoshino K,Sato K,Yoshida A,Hayakawa I,Bures MG,Shen LLdoi
10.1128/AAC.40.8.1775subject
Has Abstractpub_date
1996-08-01 00:00:00pages
1775-84issue
8eissn
0066-4804issn
1098-6596journal_volume
40pub_type
杂志文章abstract::The antibacterial activity of RU 64004, a new ketolide, was evaluated against more than 600 bacterial strains and was compared with those of various macrolides and pristinamycin. RU 64004 had good activity against multiresistant pneumococci, whether they were erythromycin A resistant or not, including penicillin-resis...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.41.10.2149
更新日期:1997-10-01 00:00:00
abstract::A hemoglobin-supplemented medium composed of Columbia agar base supplemented with 1% hemoglobin and 1% Polyvitex was used to investigate the in vitro activity of 29 antimicrobial agents against Capnocytophaga species. Clindamycin was the most active agent, with all strains being inhibited by 0.06 microgram/ml or less....
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.30.5.739
更新日期:1986-11-01 00:00:00
abstract::Staphylococcus aureus bacteremia (SAB) causes high rates of morbidity and death. Several studies in academic health settings have demonstrated that consultations from infectious diseases specialists improve the quality of care and clinical outcomes for SAB. Few data that describe the impact in resource-limited setting...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00439-16
更新日期:2016-09-23 00:00:00
abstract::Dihydroorotate dehydrogenase (DHOD) is a pyrimidine biosynthetic enzyme which is usually directly linked to the mitochondrial respiratory chain. Antimalarial naphthoquinones such as atovaquone (566c80) inhibit malarial DHOD by inhibiting electron transport. Since atovaquone also has therapeutic activity against Pneumo...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.39.2.325
更新日期:1995-02-01 00:00:00
abstract::Eltrombopag is an orally bioavailable thrombopoietin receptor agonist approved for the treatment of thrombocytopenia associated with chronic immune (idiopathic) thrombocytopenic purpura and chronic hepatitis C virus (HCV) infection. This study evaluated the potential drug-drug interactions between eltrombopag and the ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章,随机对照试验
doi:10.1128/AAC.03091-14
更新日期:2014-11-01 00:00:00
abstract::Intermittent preventive treatment in infants with sulfadoxine-pyrimethamine (IPTi-SP) reduces malaria episodes by 20 to 59% across Africa. This protective efficacy, however, may be affected by the high frequency of malnutrition in African infants. We analyzed the impact of malnutrition as defined by anthropometry on t...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章,随机对照试验
doi:10.1128/AAC.01723-08
更新日期:2009-05-01 00:00:00
abstract::Here, we report the first detection of carbapenemase-producing Escherichia coli in Alaska and in wildlife in the United States. Wild bird (gull) feces sampled at three locations in Southcentral Alaska yielded isolates that harbored plasmid-encoded blaKPC-2 or chromosomally encoded blaOXA-48 and genes associated with a...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00758-19
更新日期:2019-07-25 00:00:00
abstract::Mercury has a long history as an antimicrobial agent effective against eukaryotic and prokaryotic organisms. Despite its prolonged use, the basis for mercury toxicity in prokaryotes is not well understood. Archaea, like bacteria, are prokaryotes but they use a simplified version of the eukaryotic transcription apparat...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.48.6.1993-1999.2004
更新日期:2004-06-01 00:00:00
abstract::The goal of the present study was to examine the ability of cytochrome P450-2C9 (CYP2C9) to activate cyclophosphamide (CPA) and elicit tumor cell death. A CYP2C9-deficient human lymphoblastoid cell line (AHH-1 cells) and a derivative cell line (H2C9 cells) stably transfected with a cDNA encoding CYP2C9 were used. The ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.44.10.2659-2663.2000
更新日期:2000-10-01 00:00:00
abstract::Ciprofloxacin activity against Leptospira interrogans serogroup icterohaemorrhagiae was studied in vitro and in an animal model. The MBC of ciprofloxacin was 0.6 microgram/ml. Three of three Syrian hamsters died 8 to 9 days after intraperitoneal challenge with 10(6) leptospires. In contrast, five of six animals given ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.33.5.788
更新日期:1989-05-01 00:00:00
abstract::The aim of this study was to investigate the variability of the voriconazole plasma level and its relationships with clinical outcomes and adverse events among liver transplant recipients to optimize the efficacy and safety of their treatment. Liver transplant recipients treated with voriconazole were included, and vo...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.01211-17
更新日期:2017-11-22 00:00:00
abstract::Staphylococcus epidermidis is a major cause of nosocomial infections because of its ability to form biofilms on the surface of medical devices. Only a few antibacterial agents are relatively active against biofilms, and rifampin, a transcription inhibitor, ranks among the most effective molecules against biofilm-relat...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00343-07
更新日期:2007-09-01 00:00:00
abstract::In this study, concentrations of amikacin in blood and bronchial secretions of 10 patients with mechanical ventilation for acute respiratory failure due to pneumonia were measured. One-half of the patients received amikacin twice daily, and the others received once-daily administration. Concentrations in bronchial sec...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 临床试验,杂志文章
doi:10.1128/aac.39.1.264
更新日期:1995-01-01 00:00:00
abstract::Four out of 143 phenotypically isoniazid-resistant but rifampin-susceptible Mycobacterium tuberculosis strains that were isolated from patients in Germany in 2011 had mutations in the rifampin resistance-determining region of rpoB. After performing drug susceptibility testing (DST) with two methods, the proportion met...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.01752-13
更新日期:2014-01-01 00:00:00
abstract::Doxycycline is an alternative antibiotic drug for the treatment of syphilis, but data on its efficacy, especially data on its efficacy against late latent syphilis, are limited. A retrospective study was conducted to evaluate the effectiveness of doxycycline for the treatment of patients with different stages of syphi...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.01092-16
更新日期:2016-12-27 00:00:00
abstract::Resistance of influenza viruses to antiviral drugs can emerge following medication or may result from natural variation. Two classes of anti-influenza virus drugs targeting either the M2 protein (amantadine and rimantadine) or neuraminidase (NA; oseltamivir and zanamivir) are currently licensed. These drugs are expect...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.01446-08
更新日期:2009-03-01 00:00:00
abstract::The Michaelis-Menten inhibitory constants (Kis) and the concentrations required for 50% inhibition of the Plasmodium falciparum dihydropteroate synthetase were determined for six sulfa drugs. These drugs inhibited the in vitro growth of P. falciparum (50% lethal concentration) at concentrations of 30 to 500 nM; these ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.35.2.267
更新日期:1991-02-01 00:00:00
abstract::The Carba NP test was evaluated against a panel of 244 carbapenemase- and non-carbapenemase-producing Enterobacteriaceae and Pseudomonas aeruginosa isolates. We confirmed the 100% specificity and positive predictive value of the test, but the sensitivity and negative predictive value were 72.5% and 69.2%, respectively...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00878-13
更新日期:2013-09-01 00:00:00
abstract::Group A streptococcus (GAS) is an important human pathogen that causes a wide spectrum of diseases, ranging from mild throat and skin infections to severe invasive diseases such as necrotizing fasciitis and streptococcal toxic shock syndrome. Dextromethorphan (DM), a dextrorotatory morphinan and a widely used antituss...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00950-10
更新日期:2011-03-01 00:00:00
abstract::High-level resistance to quinolones has previously been shown to occur in Campylobacter spp. both in vitro and in patients treated with quinolones. We have selected isolates that are resistant to quinolones by plating cells from a susceptible C. jejuni strain, UA535, on medium containing nalidixic acid at 32 microgram...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.35.5.840
更新日期:1991-05-01 00:00:00
abstract::Aspergillus fumigatus is a leading cause of death in immunocompromised patients and a frequent colonizer of the respiratory tracts of asthma and cystic fibrosis (CF) patients. Biofilms enable bacteria and yeasts to persist in infections and can contribute to antimicrobial resistance. We investigated the ability of A. ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.00234-08
更新日期:2008-11-01 00:00:00
abstract::Cyclic peptides with an even number of alternating d,l-alpha-amino acid residues are known to self-assemble into organic nanotubes. Such peptides previously have been shown to be stable upon protease treatment, membrane active, and bactericidal and to exert antimicrobial activity against Staphylococcus aureus and othe...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.49.8.3302-3310.2005
更新日期:2005-08-01 00:00:00
abstract::Analogues based on the insect cecropin-bee melittin hybrid peptide (CEME) were studied and analyzed for activity and salt resistance. The new variants were designed to have an increase in amphipathic alpha-helical content (CP29 and CP26) and in overall positive charge (CP26). The alpha-helicity of these peptides was d...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.43.7.1542
更新日期:1999-07-01 00:00:00
abstract::Human cytomegalovirus (HCMV) infection does not generally cause problems in the immunocompetent adult but can result in severe clinical disease in the fetus, neonate, and immunocompromised host. Ganciclovir (GCV), the agent currently used to treat most HCMV infections, has resulted in much therapeutic success; however...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.44.6.1506-1511.2000
更新日期:2000-06-01 00:00:00
abstract::High-performance liquid chromatography was used to determine the penetration of 19 antimicrobial agents into human polymorphonuclear leukocytes. The ratios of the intracellular concentration to the extracellular concentration of ampicillin, piperacillin, cefazolin, ceftizoxime, cefpimizole, and ceftazidime were all le...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.31.12.1904
更新日期:1987-12-01 00:00:00
abstract::Fifty-seven cultures of Haemophilus influenzae were tested for production of beta-lactamase by use of a modified, 1-min test. Only the 24 cultures that were ampicillin resistant, whether type b or not, yielded positive results for the enzyme; all ampicillin-susceptible isolates were uniformly negative. The beta-lactam...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.9.1.196
更新日期:1976-01-01 00:00:00
abstract::The ponA gene of Mycobacterium smegmatis encodes a 95-kDa penicillin binding protein, PBP1, that is similar to PBP1s of Mycobacterium tuberculosis and Mycobacterium leprae. Transposon disruption of ponA in M. smegmatis resulted in a PBP1-deficient mutant that was sensitive to beta-lactam antibiotics, was more permeabl...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.43.12.3011
更新日期:1999-12-01 00:00:00
abstract::The post-β-lactamase-inhibitor effect (PBLIE) of tazobactam combined with ceftolozane was evaluated by time-kill assays on two clinical Escherichia coli strains producing CTX-M-15 with or without TEM-1. The organisms were exposed (2 h) to 4 μg/ml/4 μg/ml of ceftolozane-tazobactam (4× MIC), 4 μg/ml of ceftolozane, and ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.02398-13
更新日期:2014-01-01 00:00:00
abstract::Chagas disease is a parasitic infection that leads to a significant public health problem in countries where the disease is endemic and where it is nonendemic. Benznidazole is the most commonly used drug for the etiological treatment of Chagas disease. Patients treated with benznidazole suffer frequent adverse drug re...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/AAC.04078-14
更新日期:2015-01-01 00:00:00
abstract::Induction of the cloned ampC Citrobacter freundii beta-lactamase in Escherichia coli by 6-aminopenicillanic acid was prevented by periplasmic TEM beta-lactamase in the same cell. In contrast, cytoplasmic TEM beta-lactamase did not prevent induction. This result implies that entry of the beta-lactam into the cytoplasm ...
journal_title:Antimicrobial agents and chemotherapy
pub_type: 杂志文章
doi:10.1128/aac.34.12.2429
更新日期:1990-12-01 00:00:00