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Multiple-Dose Pharmacokinetics and Safety of a Novel Broad-Spectrum Cephalosporin (BAL5788) in Healthy Volunteers. Anne Schmitt-Hoffmann, 2004.BAL5788 is the water-soluble prodrug of BAL9141, a novel broad-spectrum cephalosporin with potent bactericidal activity against methicillin-resistant Staphylococcus aureus (MRSA) and penicillin-resistant Streptococcus pneumoniae . Safety and pharmacokinetic data from a multiple-dose study with 16 healthy male volunteers are reported . Subjects were randomized to receive BAL5788 at 500 or 750 mg (as BAL9141 equivalents; n = 6 subjects per dose) or placebo (n = 2 subjects per dose) . The doses were given as 200-ml infusions over 30 min once daily on days 1 and 8 and twice daily on days 2 to 7 . BAL5788 was well tolerated, with no severe or serious adverse events (AEs) or dosing-related changes in laboratory parameters, electrocardiographic findings, or vital signs . Drug accumulation in plasma was negligible during the dosing period . The results of pharmacokinetic analyses agreed well with data reported from a previous single-ascending-dose study . The elimination half-life of BAL9141 was about 3 h . The volume of distribution at steady state was equal to the volume of the adult extracellular water compartment . BAL9141 was predominantly eliminated in urine, and renal clearance of the free drug corresponded to the normal glomerular filtration rate in adults . After multiple infusions of 750 mg, the mean concentrations of BAL9141 in plasma exceeded the MIC at which 100% of MRSA isolates are inhibited (4 µg/ml) for approximately 7 to 9 h, corresponding to 58 to 75% of a 12-h dosing interval . Evolutionary Analysis by Whole-Genome Comparisons. Arvind K. Bansal, 2002.A total of 37 complete genome sequences of bacteria, archaea, and eukaryotes were compared . The percentage of orthologous genes of each species contained within any of the other 36 genomes was established . In addition, the mean identity of the orthologs was calculated . Several conclusions result: (i) a greater absolute number of orthologs of a given species is found in larger species than in smaller ones; (ii) a greater percentage of the orthologous genes of smaller genomes is contained in other species than is the case for larger genomes, which corresponds to a larger proportion of essential genes; (iii) before species can be specifically related to one another in terms of gene content, it is first necessary to correct for the size of the genome; (iv) eukaryotes have a significantly smaller percentage of bacterial orthologs after correction for genome size, which is consistent with their placement in a separate domain; (v) the archaebacteria are specifically related to one another but are not significantly different in gene content from the bacteria as a whole; (vi) determination of the mean identity of all orthologs (involving hundreds of gene comparisons per genome pair) reduces the impact of errors in misidentification of orthologs and to misalignments, and thus it is far more reliable than single gene comparisons; (vii) however, there is a maximum amount of change in protein sequences of 37% mean identity, which limits the use of percentage sequence identity to the lower taxa, a result which should also be true for single gene comparisons of both proteins and rRNA; (viii) most of the species that appear to be specifically related based upon gene content also appear to be specifically related based upon the mean identity of orthologs; (ix) the genes of a majority of species considered in this study have diverged too much to allow the construction of all-encompassing evolutionary trees . However, we have shown that eight species of gram-negative bacteria, six species of gram-positive bacteria, and eight species of archaebacteria are specifically related in terms of gene content, mean identity of orthologs, or both . DpiA Binding to the Replication Origin of Escherichia coli Plasmids and Chromosomes Destabilizes Plasmid Inheritance and Induces the Bacterial SOS Response. Christine Miller, 2003.The dpiA and dpiB genes of Escherichia coli, which are orthologs of genes that regulate citrate uptake and utilization in Klebsiella pneumoniae, comprise a two-component signal transduction system that can modulate the replication of and destabilize the inheritance of pSC101 and certain other plasmids . Here we show that perturbed replication and inheritance result from binding of the effector protein DpiA to A+T-rich replication origin sequences that resemble those in the K . pneumoniae promoter region targeted by the DpiA ortholog, CitB . Consistent with its ability to bind to A+T-rich origin sequences, overproduction of DpiA induced the SOS response in E . coli, suggesting that chromosomal DNA replication is affected . Bacteria that overexpressed DpiA showed an increased amount of DNA per cell and increased cell size—both also characteristic of the SOS response . Concurrent overexpression of the DNA replication initiation protein, DnaA, or the DNA helicase, DnaB—both of which act at A+T-rich replication origin sequences in the E . coli chromosome and DpiA-targeted plasmids—reversed SOS induction as well as plasmid destabilization by DpiA . Our finding that physical and functional interactions between DpiA and sites of replication initiation modulate DNA replication and plasmid inheritance suggests a mechanism by which environmental stimuli transmitted by these gene products can regulate chromosomal and plasmid dynamics .
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