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LB11058, a New Cephalosporin with High Penicillin-Binding Protein 2a Affinity and Activity in Experimental Endocarditis Due to Homogeneously Methicillin-Resistant Staphylococcus aureus. Jacques Vouillamoz, 2004.LB11058 is a new synthetic cephalosporin with good affinity for staphylococcal penicillin-binding protein 2a (PBP2a) . LB11058 was tested in vitro and in rats with experimental aortic endocarditis against three methicillin-resistant Staphylococcus aureus (MRSA) strains, one penicillinase-negative strain (strain COL), and two penicillinase-producing strains (COL-Bla+ and P8-Hom) . The MICs of LB11058 for the organisms were 1 mg/liter . The MICs of vancomycin and ceftriaxone were 1 and  64 mg/liter, respectively . In population analysis profiles, none of the MRSA strains grew at
2 mg of LB11058/liter . Rats with endocarditis were treated for 5 days . LB11058 was highly bound to serum proteins in rats (98%) . However, binding was saturable above a threshold of 250 mg/liter . Therefore, continuous concentrations of 250 mg/liter in serum were infused to ensure a free fraction (5 mg/liter) above the drug's MIC for the entire infusion period . Control treatments included simulation of human serum kinetics produced by intravenous vancomycin (1 g twice daily, free drug concentration above MIC,
90% of infusion period) or ceftriaxone (2 g/24 h, free drug concentrations above the MIC, 0% of infusion period) . LB11058 successfully treated 10 of 10 (100%) and 13 of 14 (93%) of rats infected with COL-Bla+ and P8-Hom, respectively . This was comparable to vancomycin (sterilization of 8 of 12 [66%] and 6 of 8 [75%] rats, respectively) . Ceftriaxone was inactive . Low concentrations of LB11058 (5 and 10 mg/liter, continuously infused) in serum were ineffective, as predicted by the pharmacodynamic parameters . At appropriate doses, LB11058 was highly effective both in vitro and in vivo . This finding supports the development of this beta-lactam with high PBP2a affinity for the treatment of MRSA infections .
Riboflavin Production in Lactococcus lactis: Potential for In Situ Production of Vitamin-Enriched Foods. Catherine Burgess, 2004.This study describes the genetic analysis of the riboflavin (vitamin B2) biosynthetic (rib) operon in the lactic acid bacterium Lactococcus lactis subsp . cremoris strain NZ9000 . Functional analysis of the genes of the L . lactis rib operon was performed by using complementation studies, as well as by deletion analysis . In addition, gene-specific genetic engineering was used to examine which genes of the rib operon need to be overexpressed in order to effect riboflavin overproduction . Transcriptional regulation of the L . lactis riboflavin biosynthetic process was investigated by using Northern hybridization and primer extension, as well as the analysis of roseoflavin-induced riboflavin-overproducing L . lactis isolates . The latter analysis revealed the presence of both nucleotide replacements and deletions in the regulatory region of the rib operon . The results presented here are an important step toward the development of fermented foods containing increased levels of riboflavin, produced in situ, thus negating the need for vitamin fortification . Three Proliferating Cell Nuclear Antigen-Like Proteins Found in the Hyperthermophilic Archaeon Aeropyrum pernix: Interactions with the Two DNA Polymerases. Katsuya Daimon, 2002.Proliferating cell nuclear antigen (PCNA) is an essential component in the eukaryotic DNA replication machinery, in which it works for tethering DNA polymerases on the DNA template to accomplish processive DNA synthesis . The PCNA also interacts with many other proteins in important cellular processes, including cell cycle control, DNA repair, and an apoptotic pathway in the domain Eucarya . We identified three genes encoding PCNA-like sequences in the genome of Aeropyrum pernix, a crenarchaeal archaeon . We cloned and expressed these genes in Escherichia coli and analyzed the gene products . All three PCNA homologs stimulated the primer extension activities of the two DNA polymerases, polymerase I (Pol I) and Pol II, identified in A . pernix to various extents, among which A . pernix PCNA 3 (ApePCNA3) provided a most remarkable effect on both Pol I and Pol II . The three proteins were confirmed to exist in the A . pernix cells . These results suggest that the three PCNAs work as the processivity factor of DNA polymerases in A . pernix cells under different conditions . In Eucarya, three checkpoint proteins, Hus1, Rad1, and Rad9, have been proposed to form a PCNA-like ring structure and may work as a sliding clamp for the translesion DNA polymerases . Therefore, it is very interesting that three active PCNAs were found in one archaeal cell . Further analyses are necessary to determine whether each PCNA has specific roles, and moreover, how they reveal different functions in the cells .
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