Journal Highlights
New Class of Antibacterial Looks Promising
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| The Fabi team |
Over the last two decades, only one new class of
antibiotics has been commercialized, and very few antibacterials with
novel mechanisms are in development. Humans and bacteria have different
mechanisms of fatty acid biosynthesis, and so David J. Payne and
coworkers of GlaxoSmithKline investigated this as a novel target.
"We have exploited these differences to identify a new class of
antibacterial agents," says Payne. "The present compounds have
exceptional activity (MIC90s as low as 0.06 µg/ml)
against S. aureus strains resistant to a variety of established
classes of antibiotics, and demonstrated in vivo efficacy against
multidrug-resistant S. aureus following oral administration.
Consequently, these molecules show some clear potential as new
therapeutic options for tackling infections caused by multidrug-resistant
pathogens. This work shows that bacterial genomics can be used to
facilitate development of new antibacterial targets and drugs."
(D. J. Payne, W. H. Miller, V. Berry, J.
Brosky, W. J. Burgess, E. Chen, W. E. DeWolf, Jr., A. P. Fosberry, R.
Greenwood, M. S. Head, D. A. Heerding, C. A. Janson, D. D. Jaworski, P.
M. Keller, P. J. Manley, T. D. Moore, K. A. Newlander, S. Pearson, B. J.
Polizzi, X. Qiu, S. F. Rittenhouse, C. Slater-Radosti, K. L. Salyers, M.
A. Seefeld, N. G. Wallis, S. B. Winram, C. C. K. Yuan, and W. F.
Huffman. 2002. Discovery of a novel and potent class of FabI-directed
antibacterial agents. Antimicrob. Agents Chemother. 46:3118-3124.) Abstract
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Sheep Scrapie in Japan: Diversity Suggests Danger
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| Horiuchi |
Scrapie is thought to have entered Japan via imported
sheep during the 1970s. Despite this short history, Motohiro Horiuchi of
the Obihiro University of Agriculture and Veterinary Medicine, Obihiro,
Japan, and others demonstrate that at least three strains exist in
Japan. "We don't know whether a single strain has branched or
whether multiple strains entered Japan," says Horiuchi.
Nonetheless, this and the high probability that bovine spongiform
encephalopathy (BSE) is caused by a strain of scrapie that jumped
species suggest the need for attentiveness to the risk that one of the
three strains could cross the species barrier into humans. Five cases of
BSE—believed to have been transmitted by imported animal materials—have
occurred in Japan, but these must be compared with the strains of
scrapie as well as with European BSE cases in order to assess the risk
in Japan, says Horiuchi. "We also need to establish fine strain
typing methods for the [BSE] agents."
(M. Horiuchi, T. Nemoto, N. Ishiguro, H.
Furuoka, S. Mohri, and M. Shinagawa. 2002. Biological and biochemical
characterization of sheep scrapie in Japan. J. Clin. Microiol.
40:3421-3426.) Abstract
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Shape of General Transcription Factor Helps Orient
RNA Polymerase II
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| Roberts |
RNA polymerase II, which transcribes DNA into RNA, needs
general transcription factors (GTFs) to help it find the promoter. One
of the GTFs, TFIIB, helps it find the start point to copy a gene. Stefan
G. E. Roberts of the University of Manchester, and the University of
Dundee, United Kingdom, and colleagues show that the shape that TFIIB
adopts when it binds to the promoter is critical in orienting RNA
polymerase II. "This ensures that it starts to copy the gene in the
right place," says Roberts. "Furthermore, the way that TFIIB
binds to the gene promoter helps to determine its shape. Our
understanding of how expression is regulated has centered on how GTFs
assemble with RNA polymerase II. Our new work highlights the importance
of changes in the shape of GTFs in this process. The next step is to
perform structural studies so that we can visualize the shape of TFIIB."
(J. A. Fairley, R. Evans, N. A. Hawkes,
and S. G. E. Roberts. 2002. Core promoter-dependent TFIIB conformation
and a role for TFIIB conformation in transcription start site selection.
Mol. Cell. Biol. 22:6697-6705.) Abstract
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Gene Linked to Down Syndrome Influences Mouse Brain
Development
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| Arbones |
The human Dyrk1A gene maps to chromosome 21 in
the Down syndrome (DS) critical region, is overexpressed in DS brains,
and is a candidate gene for some of the neurological defects seen in DS
patients. Maria L. Arbones of the Centre de Regulacio Genomica,
Barcelona, Spain, and others have created a strain of mice with
mutations in that gene. Mice with one copy of Dyrk1A are small,
with a brain that is 30% smaller than normal. "Our results indicate
that Dyrk1A is involved in cellular mechanisms that control
growth and suggests an important role for this protein during brain
development," says Arbones. "Interestingly, flies with
mutations in the homologous gene have small brains. We think this mouse
model will illuminate the role of Dyrk1A in brain function and
development." The researchers are studying questions of whether Dyrk1A
regulates the number of neurons, whether there is a defect in
differentiation, and the functional consequences of the morphological
alterations.
(V. Fotaki, M. Dierssen, S. Alcantara, S.
Martinez, E. Marti, C. Casas, J. Visa, E. Soriano, X. Estivill, and M.
L. Arbones. 2002. Dyrk1A haploinsufficiency affects viability and
causes developmental delay and abnormal brain morphology in mice. Mol.
Cell. Biol. 22:6636-6647.) Abstract
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Even Fungi Need Proper Nutrition
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| Howlett |
Lack of isocitrate lyase, which normal blackleg fungus
produces endogenously, due to a defect in that gene, causes Leptosphaeria
maculans to "run out of steam before it can establish a serious
infection of canola," says Barbara Howlett of the University of
Melbourne, Australia. "Its growth rate increased when we added a
simple carbon source (glucose); this finding was consistent with the
role of this enzyme in using fats as an energy source. Since isocitrate
lyase is absent from animals, drugs acting against its gene product
would be safe to use on humans. Unlike animals, plants contain an
isocitrate lyase gene, and so future work examining chemical inhibitors
of isocitrate lyase will focus on the fungal specificity of such
chemicals. Our discovery highlights the importance of the nutrition of
pathogens during the disease process. We now will focus on precisely
what nutrients the fungus uses during growth in canola."
(A. Idnurm and B. J. Howlett. 2002.
Isocitrate lyase is essential for pathogenicity of the fungus Leptosphaeria
maculans to canola (Brassica napus). Euk. Cell
1:719-724.)
New Data on Biofilm Behavior
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| Costerton, Purevdorj,
Stoodley |
The growth of biofilms is influenced by flow rate in
their environment, and quorum sensing is not as critical as once
believed, according to Paul Stoodley and colleagues at Montana State
University, Bozeman. The researchers also showed that biofilms can flow
along the walls of flow cells, the rate of flow varying with that of
water through the flow cells. "The flow of biofilms along pipe
walls may... be an important consideration in infection from venous
catheters, dental unit water lines, or dialysis machines," the
researchers write. "...Our results suggest that [quorum sensing]
alone is not necessarily required for biofilm formation and that other
factors of the growth environment, such as nutrients and hydrodynamic
conditions, can play a role of equal if not greater significance in
determining the biofilm structure and behavior."
(B. Purevdorj, J. W. Costerton, and P.
Stoodley. 2002. Influence of hydrodynamics and cell signaling on the
structure and behavior of Pseudomonas aeruginosa biofilms. Appl.
Environ. Microbiol. 68:4457-4464.) Abstract
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