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      Don’t let sleeping dogmas lie: new views of peptidoglycan synthesis and its regulation : New views on peptdigoglycan synthesis

      , , ,
      Molecular Microbiology
      Wiley-Blackwell

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          Abstract

          <p id="P1">Bacterial cell wall synthesis is the target for some of our most powerful antibiotics and has thus been the subject of intense research focus for more than 50 years. Surprisingly, we still lack a fundamental understanding of how bacteria build, maintain and expand their cell wall. Due to technical limitations, directly testing hypotheses about the coordination and biochemistry of cell wall synthesis enzymes or architecture has been challenging, and interpretation of data has therefore often relied on circumstantial evidence and implicit assumptions. A number of recent papers have exploited new technologies, like single molecule tracking and real-time, high resolution temporal mapping of cell wall synthesis processes, to address fundamental questions of bacterial cell wall biogenesis. The results have challenged established dogmas and it is therefore timely to integrate new data and old observations into a new model of cell wall biogenesis in rod-shaped bacteria. </p><p id="P2">The cell wall is an essential component of most bacterial cells, and has been a major focus of research for the last 50 years. Despite this intense research, we still have an incomplete understanding of how bacteria construct their cell wall. In this MicroReview, we will summarize important new data generated in the last few years, reexamine some established ideas in the field, and propose a new model of cell wall biogenesis in rod-shaped bacteria. </p>

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          Wall teichoic acids of gram-positive bacteria.

          The peptidoglycan layers of many gram-positive bacteria are densely functionalized with anionic glycopolymers known as wall teichoic acids (WTAs). These polymers play crucial roles in cell shape determination, regulation of cell division, and other fundamental aspects of gram-positive bacterial physiology. Additionally, WTAs are important in pathogenesis and play key roles in antibiotic resistance. We provide an overview of WTA structure and biosynthesis, review recent studies on the biological roles of these polymers, and highlight remaining questions. We also discuss prospects for exploiting WTA biosynthesis as a target for new therapies to overcome resistant infections.
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            Beta-lactam antibiotics induce a lethal malfunctioning of the bacterial cell wall synthesis machinery.

            Penicillin and related beta-lactams comprise one of our oldest and most widely used antibiotic therapies. These drugs have long been known to target enzymes called penicillin-binding proteins (PBPs) that build the bacterial cell wall. Investigating the downstream consequences of target inhibition and how they contribute to the lethal action of these important drugs, we demonstrate that beta-lactams do more than just inhibit the PBPs as is commonly believed. Rather, they induce a toxic malfunctioning of their target biosynthetic machinery involving a futile cycle of cell wall synthesis and degradation, thereby depleting cellular resources and bolstering their killing activity. Characterization of this mode of action additionally revealed a quality control function for enzymes that cleave bonds in the cell wall matrix. The results thus provide insight into the mechanism of cell wall assembly and suggest how best to interfere with the process for future antibiotic development.
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              Prokaryotic origin of the actin cytoskeleton.

              It was thought until recently that bacteria lack the actin or tubulin filament networks that organize eukaryotic cytoplasm. However, we show here that the bacterial MreB protein assembles into filaments with a subunit repeat similar to that of F-actin-the physiological polymer of eukaryotic actin. By elucidating the MreB crystal structure we demonstrate that MreB and actin are very similar in three dimensions. Moreover, the crystals contain protofilaments, allowing visualization of actin-like strands at atomic resolution. The structure of the MreB protofilament is in remarkably good agreement with the model for F-actin, showing that the proteins assemble in identical orientations. The actin-like properties of MreB explain the finding that MreB forms large fibrous spirals under the cell membrane of rod-shaped cells, where they are involved in cell-shape determination. Thus, prokaryotes are now known to possess homologues both of tubulin, namely FtsZ, and of actin.
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                Author and article information

                Journal
                Molecular Microbiology
                Molecular Microbiology
                Wiley-Blackwell
                0950382X
                December 2017
                December 26 2017
                : 106
                : 6
                : 847-860
                Article
                10.1111/mmi.13853
                5720918
                28975672
                113246f4-9d46-4b0e-93f2-ebe61c3d3ccf
                © 2017

                http://doi.wiley.com/10.1002/tdm_license_1.1

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