Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0348321 (Haemophilus)
15,372 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We developed a diagnostic array of oligonucleotide probes targeting species-specific variable regions of the genes encoding topoisomerases GyrB and ParE of respiratory bacterial pathogens. Suitable broad-range primer sequences were designed based on alignment of gyrB/parE sequences from nine different bacterial species. These species included Corynebacterium diphtheriae, Fusobacterium necrophorum, Haemophilus influenzae, Legionella pneumophila, Moraxella catarrhalis, Mycoplasma pneumoniae, Staphylococcus aureus, Streptococcus pneumoniae, and Streptococcus pyogenes. Specific probe sequences were selected by comparative analysis against the European Bioinformatics Database, as well as gyrB/parE sequences generated for this study. To verify specificity, at least six initial oligonucleotide probe sequences per bacterial species were tested by hybridization on a solid glass support using culture collection strains as templates. Finally, three oligonucleotide probes per bacterial species were utilized to examine 65 middle ear fluid and 29 throat swab samples. The sensitivities of the developed assay compared to classic culture from middle ear fluid samples for H. influenzae, M. catarrhalis, and S. pneumoniae were 96 (93 for culture), 73 (93 for culture), and 100% (78% for culture), respectively. No cross-reactivity with bacterial species belonging to the normal oral flora was observed when the 29 throat swab samples were studied. The sensitivity of the assay to detect S. pyogenes from these samples was 93% (80% for culture). These results provide a proof of concept for the diagnostic use of microarray technology based on broad-range topoisomerase gene amplification, followed by hybridization and specific detection of bacterial species.
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PMID:Use of an oligonucleotide array for laboratory diagnosis of bacteria responsible for acute upper respiratory infections. 1536 22

Gemifloxacin is a synthetic fluoroquinolone antimicrobial agent exhibiting potent activity against most gram-negative and gram-positive organisms, such as the important community-acquired respiratory pathogens Streptococcus pneumoniae (including multidrug-resistant S. pneumoniae), Haemophilus influenzae , and Moraxella catarrhalis . The agent's mechanism of action involves dual targeting of two essential bacterial enzymes: DNA gyrase and topoisomerase IV. Gemifloxacin was approved by the Food and Drug Administration in April 2003 for treatment of community-acquired pneumonia and acute bacterial exacerbation of chronic bronchitis. The drug has an oral bioavailability of approximately 71%. Approximately 20-35% of gemifloxacin is excreted unchanged in the urine after 24 hours. The elimination half-life of gemifloxacin is 6-8 hours in patients with normal renal function, supporting once-daily dosing. The 24-hour free-drug area under the plasma concentration-time curve:minimum inhibitory concentration ratio (fAUC(0-24):MIC) associated with efficacy, based on results from in vitro and animal models of infection, is approximately 30. With a mean fAUC(0-24) of approximately 3 microg*hour/ml (35% of total AUC(0-24) of 8.4) and a median S. pneumoniae MIC for 90% of tested strains of 0.03, a fAUC(0-24):MIC ratio of 100 would be expected after standard dosing (320 mg once/day). In clinical studies involving both hospitalized and outpatient populations, gemifloxacin has been highly effective in the treatment of community-acquired pneumonia and acute exacerbation of chronic bronchitis. Clinical success rates ranged from 93.9-95.9% in patients with community-acquired pneumonia and 96.1-97.5% in those with acute exacerbation of chronic bronchitis. Gemifloxacin is well tolerated; the frequency of adverse events with this agent is low. Most adverse events are mild-to-moderate in severity, with diarrhea (< 4%), nausea and rash (< 3%), and headache (< 2%) most commonly reported. Drug interactions with gemifloxacin are not common, although absorption is greatly reduced when given with divalent and trivalent cation-containing compounds, such as antacids. Due to its potent activity against many common gram-positive and gram-negative respiratory pathogens, its proven clinical efficacy, and its favorable safety profile, gemifloxacin is a highly effective empiric treatment for community-acquired lower respiratory tract infections.
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PMID:Gemifloxacin for the treatment of respiratory tract infections: in vitro susceptibility, pharmacokinetics and pharmacodynamics, clinical efficacy, and safety. 1589 34

Quinolone-resistant Streptococcus agalactiae bacteria were recovered from single-patient isolates and found to contain mutations in the gyrase and topoisomerase IV genes. Pulsed-field gel electrophoresis demonstrated that four isolates from the same long-term care facility were closely related; in seven cases, quinolone-resistant Haemophilus influenzae and S. agalactiae bacteria were isolated from the same patient.
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PMID:Fluoroquinolone-resistant Streptococcus agalactiae: epidemiology and mechanism of resistance. 1591 53

PD-140248 is an isomerase inhibitor and topoisomerase II inhibitor under development by Parke-Davis and Co as a potential treatment for bacterial infection. Although no details of active development have been published in the scientific literature since 1996, in September 1999, the company confirmed that PD-140248 is still in active development [338530]. The compound is one of two new pyrrolidinyl naphthyridines (the other compound being PD-131628) with a broad spectrum of antibacterial activity, including activity against quinolone-resistant bacteria. PD-140248 demonstrates strong in vitro activity, particularly against Gram-positive bacteria, such as quinolone-susceptible Staphylococcus aureus (S aureus), Staphylococcus epidermidis (S epidermidis), Staphylococcus haemolyticus (S haemolyticus), methicillin- and ciprofloxacin-resistant S aureus, Streptococcus species, Streptococcus pneumoniae (S pneumoniae) and Enterococcus faecalis (E faecalis). An MIC90 value of 0.015 microg/ml was obtained against Haemophilus influenzae (H influenzae) and Moraxella catarrhalis [160129]. The (3R,1S) enantiomer, PD-140248, demonstrated a 1- to 10-fold enhanced activity against Gram-positive and Gram-negative organisms in vitro and in vivo compared to its stereoisomers, and has thus been targeted for further preclinical studies [133377].
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PMID:PD-140248 (Parke-Davis & Co). 1610 42

Antibiotics with novel mechanisms of action are becoming increasingly important in the battle against bacterial resistance to all currently used classes of antibiotics. Bacterial DNA gyrase and topoisomerase IV (topoIV) are the familiar targets of fluoroquinolone and coumarin antibiotics. Here we present the characterization of two members of a new class of synthetic bacterial topoII ATPase inhibitors: VRT-125853 and VRT-752586. These aminobenzimidazole compounds were potent inhibitors of both DNA gyrase and topoIV and had excellent antibacterial activities against a wide spectrum of problematic pathogens responsible for both nosocomial and community-acquired infections, including staphylococci, streptococci, enterococci, and mycobacteria. Consistent with the novelty of their structures and mechanisms of action, antibacterial potency was unaffected by commonly encountered resistance phenotypes, including fluoroquinolone resistance. In time-kill assays, VRT-125853 and VRT-752586 were bactericidal against Staphylococcus aureus, Streptococcus pneumoniae, Enterococcus faecalis, and Haemophilus influenzae, causing 3-log reductions in viable cells within 24 h. Finally, similar to the fluoroquinolones, relatively low frequencies of spontaneous resistance to VRT-125853 and VRT-752586 were found, a property consistent with their in vitro dual-targeting activities.
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PMID:In vitro characterization of the antibacterial spectrum of novel bacterial type II topoisomerase inhibitors of the aminobenzimidazole class. 1656 33

A structure-guided drug design approach was used to optimize a novel series of aminobenzimidazoles that inhibit the essential ATPase activities of bacterial DNA gyrase and topoisomerase IV and that show potent activities against a variety of bacterial pathogens. Two such compounds, VRT-125853 and VRT-752586, were characterized for their target specificities and preferences in bacteria. In metabolite incorporation assays, VRT-125853 inhibited both DNA and RNA synthesis but had little effect on protein synthesis. Both compounds inhibited the maintenance of negative supercoils in plasmid DNA in Escherichia coli at the MIC. Sequencing of DNA corresponding to the GyrB and ParE ATP-binding regions in VRT-125853- and VRT-752586-resistant mutants revealed that their primary target in Staphylococcus aureus and Haemophilus influenzae was GyrB, whereas in Streptococcus pneumoniae it was ParE. In Enterococcus faecalis, the primary target of VRT-125853 was ParE, whereas for VRT-752586 it was GyrB. DNA transformation experiments with H. influenzae and S. aureus proved that the mutations observed in gyrB resulted in decreased susceptibilities to both compounds. Novobiocin resistance-conferring mutations in S. aureus, H. influenzae, and S. pneumoniae were found in gyrB, and these mutants showed little or no cross-resistance to VRT-125853 or VRT-752586 and vice versa. Furthermore, gyrB and parE double mutations increased the MICs of VRT-125853 and VRT-752586 significantly, providing evidence of dual targeting. Spontaneous frequencies of resistance to VRT-752586 were below detectable levels (<5.2x10(-10)) for wild-type E. faecalis but were significantly elevated for strains containing single and double target-based mutations, demonstrating that dual targeting confers low levels of resistance emergence and the maintenance of susceptibility in vitro.
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PMID:Dual targeting of GyrB and ParE by a novel aminobenzimidazole class of antibacterial compounds. 1711 75

PD 0305970 and PD 0326448 are new bacterial gyrase and topoisomerase inhibitors (quinazoline-2,4-diones) that possess outstanding in vitro and in vivo activities against a wide spectrum of bacterial species including quinolone- and multidrug-resistant gram-positive and fastidious organism groups. The respective MICs (microg/ml) for PD 0305970 capable of inhibiting>or=90% of bacterial strains tested ranged from 0.125 to 0.5 versus staphylococci, 0.03 to 0.06 versus streptococci, 0.25 to 2 versus enterococci, and 0.25 to 0.5 versus Moraxella catarrhalis, Haemophilus influenzae, Listeria monocytogenes, Legionella pneumophila, and Neisseria spp. PD 0326448 MIC90s were generally twofold higher versus these same organism groups. Comparative quinolone MIC90 values were 4- to 512-fold higher than those of PD 0305970. In testing for frequency of resistance, PD 0305970 and levofloxacin showed low levels of development of spontaneous resistant mutants versus both Staphylococcus aureus and Streptococcus pneumoniae. Unlike quinolones, which target primarily gyrA and parC, analysis of resistant mutants in S. pneumoniae indicates that the likely targets of PD 0305970 are gyrB and parE. PD 0305970 demonstrated rapid bactericidal activity by in vitro time-kill testing versus streptococci. This bactericidal activity carried over to in vivo testing, where PD 0305970 and PD 0326448 displayed outstanding Streptococcus pyogenes 50% protective doses (PD50s) (oral dosing) of 0.7 and 3.6 mg/kg, respectively (ciprofloxacin and levofloxacin PD50s were>100 and 17.7 mg/kg, respectively). PD 0305970 was also potent in a pneumococcal pneumonia mouse infection model (PD50=3.2 mg/kg) and was 22-fold more potent than levofloxacin.
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PMID:In vitro and in vivo activities of PD 0305970 and PD 0326448, new bacterial gyrase/topoisomerase inhibitors with potent antibacterial activities versus multidrug-resistant gram-positive and fastidious organism groups. 1726 23

We established a real-time PCR assay with melting curve analysis to rapidly genotype quinolone resistance-determining regions (QRDRs) of gyrase A and topoisomerase IV genes in Haemophilus influenzae. This assay is a useful tool for the detection of fluoroquinolone resistance and for the early detection of preexisting QRDR mutations.
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PMID:Melting curve analysis for rapid detection of topoisomerase gene mutations in Haemophilus influenzae. 1912 13

Besifloxacin hydrochloride ophthalmic suspension 0.6% (Besivance) is a recently approved fluoroquinolone for the topical treatment of bacterial conjunctivitis. The drug is rapidly bactericidal against common bacterial pathogens causing conjunctivitis, i.e., coagulase-negative Staphylococcus, Streptococcus pneumoniae, Staphylococcus aureus and Haemophilus influenzae as well as against other less common organisms. In addition to being a potent agent against Gram-positive and Gram-negative pathogens including those resistant to other fluoroquinolones, besifloxacin has balanced DNA gyrase and topoisomerase IV activity, which should slow the development of resistance. Topical administration achieves high sustained concentrations in human tears and good ocular tissue penetration in animals while demonstrating an excellent safety profile. Besifloxacin's pharmacokinetic and pharmacodynamic characteristics meet the criteria for successful eradication of many Gram-positive and Gram-negative bacteria while demonstrating minimal systemic exposure. The biochemical properties, achievement of target pharmacokinetic/pharmacodynamic goals and the restriction of besifloxacin to topical ophthalmic use should result in slower development of bacterial resistance, making besifloxacin a new, appealing option for empiric therapy in acute bacterial conjunctivitis.
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PMID:Besifloxacin ophthalmic suspension for bacterial conjunctivitis. 1992 24

Besifloxacin is a novel fluoroquinolone that, like other fluoroquinolones, acts by inhibiting the essential bacterial enzymes DNA gyrase and topoisomerase IV. Topical besifloxacin ophthalmic suspension 0.6% is indicated for use in patients with bacterial conjunctivitis caused by susceptible bacteria. Besifloxacin had in vitro activity against a broad spectrum of Gram-positive and -negative bacteria that commonly cause ocular infections (e.g. Haemophilus influenzae, Staphylococcus aureus, S. epidermidis and Streptococcus pneumoniae), including drug-resistant strains. In two randomized, double-blind, multicentre trials, besifloxacin ophthalmic suspension 0.6% administered at the recommended dose for 5 days in patients aged > or =1 year with bacterial conjunctivitis was significantly (p < 0.01) more effective than vehicle in terms of clinical resolution and microbial eradication rates (coprimary endpoints) at study visit two (day 5+/-1) or three (day 8 or 9) [primary timepoints]. Besifloxacin ophthalmic suspension 0.6% was noninferior to moxifloxacin ophthalmic solution 0.5% in patients aged > or =1 year with bacterial conjunctivitis with regard to clinical resolution (58.3% vs 59.4%) and microbial eradication (93.3% vs 91.1%) rates on day 5 +/- 1 of treatment (coprimary endpoints) in a randomized, double-blind, multicentre trial; both drugs were administered at a dosage of one drop in the affected eye(s) three times daily for 5 days. Besifloxacin ophthalmic suspension 0.6% was generally well tolerated in clinical trials, with most adverse events being mild in severity. The tolerability profile of besifloxacin ophthalmic suspension 0.6% was similar to that of moxifloxacin ophthalmic solution 0.5%.
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PMID:Besifloxacin ophthalmic suspension 0.6%. 2003 Apr 27


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