Regulation and function of class A Penicillin-binding proteins
TL;DR: It is hypothesize that class A PBP function is essential in walled bacteria unless they have (a) SEDS protein(s) capable of replacing their function.
About: This article is published in Current Opinion in Microbiology.The article was published on 2021-02-18. It has received 24 citations till now. The article focuses on the topics: Penicillin binding proteins & Peptidoglycan.
Citations
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TL;DR: Progress made toward understanding the translocation of Lipid II across the cytoplasmic membrane by the MurJ flippase is highlighted as well as the recent discovery of a novel class of PG polymerases, the SEDS (shape, elongation, division, and sporulation) glycosyltransferases RodA and FtsW.
Abstract: The peptidoglycan (PG) cell wall is an extra-cytoplasmic glycopeptide polymeric structure that protects bacteria from osmotic lysis and determines cellular shape. Since the cell wall surrounds the cytoplasmic membrane, bacteria must add new material to the PG matrix during cell elongation and division. The lipid-linked precursor for PG biogenesis, Lipid II, is synthesized in the inner leaflet of the cytoplasmic membrane and is subsequently translocated across the bilayer so that the PG building block can be polymerized and cross-linked by complex multiprotein machines. This review focuses on major discoveries that have significantly changed our understanding of PG biogenesis in the past decade. In particular, we highlight progress made toward understanding the translocation of Lipid II across the cytoplasmic membrane by the MurJ flippase, as well as the recent discovery of a novel class of PG polymerases, the SEDS (shape, elongation, division, and sporulation) glycosyltransferases RodA and FtsW. Since PG biogenesis is an effective target of antibiotics, these recent developments may lead to the discovery of much-needed new classes of antibiotics to fight bacterial resistance.
18 citations
TL;DR: In this article, the function of cell wall synthesis enzymes in the plant pathogen Agrobacterium tumefaciens was investigated using fluorescent d-amino acid dipeptide (FDAAD) probes.
Abstract: Members of the Rhizobiales are polarly growing bacteria that lack homologs of the canonical Rod complex. To investigate the mechanisms underlying polar cell wall synthesis, we systematically probed the function of cell wall synthesis enzymes in the plant pathogen Agrobacterium tumefaciens. The development of fluorescent d-amino acid dipeptide (FDAAD) probes, which are incorporated into peptidoglycan by penicillin-binding proteins in A. tumefaciens, enabled us to monitor changes in growth patterns in the mutants. Use of these fluorescent cell wall probes and peptidoglycan compositional analysis demonstrate that a single class A penicillin-binding protein is essential for polar peptidoglycan synthesis. Furthermore, we find evidence of an additional mode of cell wall synthesis that requires ld-transpeptidase activity. Genetic analysis and cell wall targeting antibiotics reveal that the mechanism of unipolar growth is conserved in Sinorhizobium and Brucella. This work provides insights into unipolar peptidoglycan biosynthesis employed by the Rhizobiales during cell elongation. IMPORTANCE While the structure and function of the bacterial cell wall are well conserved, the mechanisms responsible for cell wall biosynthesis during elongation are variable. It is increasingly clear that rod-shaped bacteria use a diverse array of growth strategies with distinct spatial zones of cell wall biosynthesis, including lateral elongation, unipolar growth, bipolar elongation, and medial elongation. Yet the vast majority of our understanding regarding bacterial elongation is derived from model organisms exhibiting lateral elongation. Here, we explore the role of penicillin-binding proteins in unipolar elongation of Agrobacterium tumefaciens and related bacteria within the Rhizobiales. Our findings suggest that penicillin-binding protein 1a, along with a subset of ld-transpeptidases, drives unipolar growth. Thus, these enzymes may serve as attractive targets for biocontrol of pathogenic Rhizobiales.
13 citations
TL;DR: A review of the key protein complexes and how they are involved in cell division in pneumococcus pneumoniae is provided in this paper, where the interaction of proteins in the divisome complex that underpin the control mechanisms for cell division and cell wall synthesis and remodelling are discussed.
Abstract: Cell division in Streptococcus pneumoniae (pneumococcus) is performed and regulated by a protein complex consisting of at least 14 different protein elements; known as the divisome. Recent findings have advanced our understanding of the molecular events surrounding this process and have provided new understanding of the mechanisms that occur during the division of pneumococcus. This review will provide an overview of the key protein complexes and how they are involved in cell division. We will discuss the interaction of proteins in the divisome complex that underpin the control mechanisms for cell division and cell wall synthesis and remodelling that are required in S. pneumoniae, including the involvement of virulence factors and capsular polysaccharides.
13 citations
TL;DR: A review of peptidoglycan assembly in Firmicutes is presented in this article, focusing on the main developments reported over the last five years for the assembly of the extracellular mesh-like polymer surrounding the bacterial cell.
12 citations
TL;DR: The updated model proposes a balance between several allosteric interactions that determine the state of septal peptidoglycan synthesis, and elaborates on and supports an earlier proposed model that describes active and inactive conformations of the septic peptidlycercan synthesis complex that are stabilized by these interactions.
Abstract: The synthesis of a peptidoglycan septum is a fundamental part of bacterial fission and is driven by a multiprotein dynamic complex called the divisome. FtsW and FtsI are essential proteins that synthesize the peptidoglycan septum and are controlled by the regulatory FtsBLQ subcomplex and the activator FtsN. However, their mode of regulation has not yet been uncovered in detail. Understanding this process in detail may enable the development of new compounds to combat the rise in antibiotic resistance. In this review, recent data on the regulation of septal peptidoglycan synthesis is summarized and discussed. Based on structural models and the collected data, multiple putative interactions within FtsWI and with regulators are uncovered. This elaborates on and supports an earlier proposed model that describes active and inactive conformations of the septal peptidoglycan synthesis complex that are stabilized by these interactions. Furthermore, a new model on the spatial organization of the newly synthesized peptidoglycan and the synthesis complex is presented. Overall, the updated model proposes a balance between several allosteric interactions that determine the state of septal peptidoglycan synthesis.
10 citations
References
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TL;DR: This Review discusses how growth of the sacculus is sensitive to mechanical force and nutritional status, and describes the roles of peptidoglycan hydrolases in generating cell shape and of D-amino acids in sacculus remodelling.
Abstract: How bacteria grow and divide while retaining a defined shape is a fundamental question in microbiology, but technological advances are now driving a new understanding of how the shape-maintaining bacterial peptidoglycan sacculus grows. In this Review, we highlight the relationship between peptidoglycan synthesis complexes and cytoskeletal elements, as well as recent evidence that peptidoglycan growth is regulated from outside the sacculus in Gram-negative bacteria. We also discuss how growth of the sacculus is sensitive to mechanical force and nutritional status, and describe the roles of peptidoglycan hydrolases in generating cell shape and of D-amino acids in sacculus remodelling.
1,097 citations
TL;DR: It is reported that, in Bacillus subtilis, this complex is functional in the absence of all known peptidoglycan polymerases, and these enzymes are core cell wall synthases of the cell elongation and division machinery, and represent attractive targets for antibiotic development.
Abstract: Elongation of rod-shaped bacteria is mediated by a dynamic peptidoglycan-synthetizing machinery called the Rod complex. Here we report that, in Bacillus subtilis, this complex is functional in the absence of all known peptidoglycan polymerases. Cells lacking these enzymes survive by inducing an envelope stress response that increases the expression of RodA, a widely conserved core component of the Rod complex. RodA is a member of the SEDS (shape, elongation, division and sporulation) family of proteins, which have essential but ill-defined roles in cell wall biogenesis during growth, division and sporulation. Our genetic and biochemical analyses indicate that SEDS proteins constitute a family of peptidoglycan polymerases. Thus, B. subtilis and probably most bacteria use two distinct classes of polymerase to synthesize their exoskeleton. Our findings indicate that SEDS family proteins are core cell wall synthases of the cell elongation and division machinery, and represent attractive targets for antibiotic development.
422 citations
TL;DR: A model is proposed in which the membrane‐associated MreBCD complex directs longitudinal cell wall synthesis in a process essential to maintain cell morphology, and a multicopy plasmid carrying the ftsQAZ genes suppressed the lethality of deletions in the mre operon.
Abstract: Summary MreB proteins of Escherichia coli , Bacillus subtilis and Caulobacter crescentus form actin-like cables lying beneath the cell surface. The cables are required to guide longitudinal cell wall synthesis and their absence leads to merodiploid spherical and inflated cells prone to cell lysis. In B. subtilis and C. crescentus , the mreB gene is essential. However, in E. coli , mreB was inferred not to be essential. Using a tight, conditional gene depletion system, we systematically investigated whether the E. coli mreBCD -encoded components were essential. We found that cells depleted of mreBCD became spherical, enlarged and finally lysed. Depletion of each mre gene separately conferred similar gross changes in cell morphology and viability. Thus, the three proteins encoded by mreBCD are all essential and function in the same morphogenetic pathway. Interestingly, the presence of a multicopy plasmid carrying the ftsQAZ genes suppressed the lethality of deletions in the mre operon. Using GFP and cell fractionation methods, we showed that the MreC and MreD proteins were associated with the cell membrane. Using a bacterial two-hybrid system, we found that MreC interacted with both MreB and MreD. In contrast, MreB and MreD did not interact in this assay. Thus, we conclude that the E. coli MreBCD form an essential membrane-bound complex. Curiously, MreB did not form cables in cell depleted for MreC, MreD or RodA, indicating a mutual interdependency between MreB filament morphology and cell shape. Based on these and other observations we propose a model in which the membrane-associated MreBCD complex directs longitudinal cell wall synthesis in a process essential to maintain cell morphology.
374 citations
TL;DR: The observations suggest that cell-wall synthesis in the presence of β-lactam antibiotics requires the cooperative functioning of the transglycosylasedomain of the native staphylococcal PBP2 and the transpeptidase domain of the P BP2A, a protein imported by S. aureus from an extra species source.
Abstract: The blanket resistance of methicillin-resistant Staphylococcus aureus to all β-lactam antibiotics—which had such a devastating impact on chemotherapy of staphylococcal infections—is related to the properties of the key component of this resistance mechanism: the “acquired” penicillin-binding protein (PBP)-2A, which has unusual low affinity for all β-lactam antibiotics. Until now, the accepted model of resistance implied that in the presence of β-lactam antibiotics in the surrounding medium, PBP2A must take over the biosynthesis of staphylococcal cell wall from the four native staphylococcal PBPs because the latter become rapidly acylated and inactivated at even low concentrations of the antibiotic. However, recent observations indicate that this model requires revision. Inactivation of the transglycosylase domain, but not the transpeptidase domain, of PBP2 of S. aureus prevents expression of β-lactam resistance, despite the presence of the low-affinity PBP2A. The observations suggest that cell-wall synthesis in the presence of β-lactam antibiotics requires the cooperative functioning of the transglycosylase domain of the native staphylococcal PBP2 and the transpeptidase domain of the PBP2A, a protein imported by S. aureus from an extra species source.
372 citations
TL;DR: It is demonstrated that PG synthases are also controlled from outside the sacculus, and the data suggest that the LpoB-PBP1B complex contributes to OM constriction during cell division.
344 citations