Journal articles: 'Peptidoglycan remodeling'

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Griffin, Matthew E., Juliel Espinosa, Jessica L. Becker, Ji-Dung Luo, Thomas S. Carroll, Jyoti K. Jha, Gary R. Fanger, and Howard C. Hang. "Enterococcus peptidoglycan remodeling promotes checkpoint inhibitor cancer immunotherapy." Science 373, no. 6558 (August 27, 2021): 1040–46. http://dx.doi.org/10.1126/science.abc9113.

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Alvarez, Laura, Akbar Espaillat, Juan A. Hermoso, Miguel A. de Pedro, and Felipe Cava. "Peptidoglycan Remodeling by the Coordinated Action of Multispecific Enzymes." Microbial Drug Resistance 20, no. 3 (June 2014): 190–98. http://dx.doi.org/10.1089/mdr.2014.0047.

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Gully, Djamel, Daniel Gargani, Katia Bonaldi, Cédric Grangeteau, Clémence Chaintreuil, Joël Fardoux, Phuong Nguyen, et al. "A Peptidoglycan-Remodeling Enzyme Is Critical for Bacteroid Differentiation in Bradyrhizobium spp. During Legume Symbiosis." Molecular Plant-Microbe Interactions® 29, no. 6 (June 2016): 447–57. http://dx.doi.org/10.1094/mpmi-03-16-0052-r.

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In response to the presence of compatible rhizobium bacteria, legumes form symbiotic organs called nodules on their roots. These nodules house nitrogen-fixing bacteroids that are a differentiated form of the rhizobium bacteria. In some legumes, the bacteroid differentiation comprises a dramatic cell enlargement, polyploidization, and other morphological changes. Here, we demonstrate that a peptidoglycan-modifying enzyme in Bradyrhizobium strains, a DD-carboxypeptidase that contains a peptidoglycan-binding SPOR domain, is essential for normal bacteroid differentiation in Aeschynomene species. The corresponding mutants formed bacteroids that are malformed and hypertrophied. However, in soybean, a plant that does not induce morphological differentiation of its symbiont, the mutation does not affect the bacteroids. Remarkably, the mutation also leads to necrosis in a large fraction of the Aeschynomene nodules, indicating that a normally formed peptidoglycan layer is essential for avoiding the induction of plant immune responses by the invading bacteria. In addition to exopolysaccharides, capsular polysaccharides, and lipopolysaccharides, whose role during symbiosis is well defined, our work demonstrates an essential role in symbiosis for yet another rhizobial envelope component, the peptidoglycan layer.

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Lee, Woo Cheol, Ahjin Jang, Jee-Young Lee, and Yangmee Kim. "Structural implication of substrate binding by peptidoglycan remodeling enzyme MepS." Biochemical and Biophysical Research Communications 583 (December 2021): 178–83. http://dx.doi.org/10.1016/j.bbrc.2021.10.050.

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Ribis, John W., Kelly A. Fimlaid, and Aimee Shen. "Differential requirements for conserved peptidoglycan remodeling enzymes duringClostridioides difficilespore formation." Molecular Microbiology 110, no. 3 (October 30, 2018): 370–89. http://dx.doi.org/10.1111/mmi.14090.

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Reuter, Jula, Christian Otten, Nicolas Jacquier, Junghoon Lee, Dominique Mengin-Lecreulx, Iris Löckener, Robert Kluj, et al. "An NlpC/P60 protein catalyzes a key step in peptidoglycan recycling at the intersection of energy recovery, cell division and immune evasion in the intracellular pathogen Chlamydia trachomatis." PLOS Pathogens 19, no. 2 (February 2, 2023): e1011047. http://dx.doi.org/10.1371/journal.ppat.1011047.

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The obligate intracellular Chlamydiaceae do not need to resist osmotic challenges and thus lost their cell wall in the course of evolution. Nevertheless, these pathogens maintain a rudimentary peptidoglycan machinery for cell division. They build a transient peptidoglycan ring, which is remodeled during the process of cell division and degraded afterwards. Uncontrolled degradation of peptidoglycan poses risks to the chlamydial cell, as essential building blocks might get lost or trigger host immune response upon release into the host cell. Here, we provide evidence that a primordial enzyme class prevents energy intensive de novo synthesis and uncontrolled release of immunogenic peptidoglycan subunits in Chlamydia trachomatis. Our data indicate that the homolog of a Bacillus NlpC/P60 protein is widely conserved among Chlamydiales. We show that the enzyme is tailored to hydrolyze peptidoglycan-derived peptides, does not interfere with peptidoglycan precursor biosynthesis, and is targeted by cysteine protease inhibitors in vitro and in cell culture. The peptidase plays a key role in the underexplored process of chlamydial peptidoglycan recycling. Our study suggests that chlamydiae orchestrate a closed-loop system of peptidoglycan ring biosynthesis, remodeling, and recycling to support cell division and maintain long-term residence inside the host. Operating at the intersection of energy recovery, cell division and immune evasion, the peptidoglycan recycling NlpC/P60 peptidase could be a promising target for the development of drugs that combine features of classical antibiotics and anti-virulence drugs.

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Jones, Greg, and Paul Dyson. "Evolution of Transmembrane Protein Kinases Implicated in Coordinating Remodeling of Gram-Positive Peptidoglycan: Inside versus Outside." Journal of Bacteriology 188, no. 21 (August 25, 2006): 7470–76. http://dx.doi.org/10.1128/jb.00800-06.

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ABSTRACT Members of a family of serine/threonine protein kinases (STPKs), unique to gram-positive bacteria, comprise an intracellular kinase domain and reiterated extracellular PASTA (for “penicillin-binding protein and serine/threonine kinase associated”) domains. PASTA domains exhibit low affinity for β-lactam antibiotics that are structurally similar to their likely normal ligands: stem peptides of unlinked peptidoglycan. The PASTA-domain STPKs are found in the actinobacteria and firmicutes and, as exemplified by PknB of Mycobacterium tuberculosis, they are functionally implicated in aspects of growth, cell division, and development. Whereas the kinase domains are well conserved, there is a wide divergence in the sequences of the multiple PASTA domains. Closer inspection reveals position-dependent evolution of individual PASTA domains: a domain at one position within a gene has a close phylogenetic relationship with a domain at a similar position in an orthologous gene, whereas neighboring domains have clearly diverged one from one another. A similar position-dependent relationship is demonstrated in the second family of proteins with multiple PASTA domains: the high-molecular-weight type II penicillin-binding protein (PBP2x) family. These transpeptidases are recruited to the division site by a localized pool of unlinked peptidoglycan. We infer that protein localization is guided by low-affinity interactions between structurally different unlinked peptidoglycan stem peptides and individual PASTA domains. The STPKs possess a greater multiplicity and diversity of PASTA domains, allowing interactions with a wider range of stem-peptide ligands. These interactions are believed to activate the intracellular kinase domain, allowing an STPK to coordinate peptidoglycan remodeling and reproduction of a complex cell wall structure.

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Chan, Jia Mun, and Joseph P. Dillard. "Neisseria gonorrhoeae Crippled Its Peptidoglycan Fragment Permease To Facilitate Toxic Peptidoglycan Monomer Release." Journal of Bacteriology 198, no. 21 (August 22, 2016): 3029–40. http://dx.doi.org/10.1128/jb.00437-16.

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ABSTRACTNeisseria gonorrhoeae(gonococci) andNeisseria meningitidis(meningococci) are human pathogens that cause gonorrhea and meningococcal meningitis, respectively. BothN. gonorrhoeaeandN. meningitidisrelease a number of small peptidoglycan (PG) fragments, including proinflammatory PG monomers, althoughN. meningitidisreleases fewer PG monomers. The PG fragments released byN. gonorrhoeaeandN. meningitidisare generated in the periplasm during cell wall remodeling, and a majority of these fragments are transported into the cytoplasm by an inner membrane permease, AmpG; however, a portion of the PG fragments are released into the extracellular environment through unknown mechanisms. We previously reported that the expression of meningococcalampGinN. gonorrhoeaereduced PG monomer release by gonococci. This finding suggested that the efficiency of AmpG-mediated PG fragment recycling regulates the amount of PG fragments released into the extracellular milieu. We determined that three AmpG residues near the C-terminal end of the protein modulate AmpG's efficiency. We also investigated the association between PG fragment recycling and release in two species of human-associated nonpathogenicNeisseria:N. siccaandN. mucosa. BothN. siccaandN. mucosarelease lower levels of PG fragments and are more efficient at recycling PG fragments thanN. gonorrhoeae. Our results suggest thatN. gonorrhoeaehas evolved to increase the amounts of toxic PG fragments released by reducing its PG recycling efficiency.IMPORTANCENeisseria gonorrhoeaeandNeisseria meningitidisare human pathogens that cause highly inflammatory diseases, althoughN. meningitidisis also frequently found as a normal member of the nasopharyngeal microbiota. NonpathogenicNeisseria, such asN. siccaandN. mucosa, also colonize the nasopharynx without causing disease. Although all four species release peptidoglycan fragments,N. gonorrhoeaeis the least efficient at recycling and releases the largest amount of proinflammatory peptidoglycan monomers, partly due to differences in the recycling permease AmpG. Studying the interplay between bacterial physiology (peptidoglycan metabolism) and pathogenesis (release of toxic monomers) leads to an increased understanding of how different bacterial species maintain asymptomatic colonization or cause disease and may contribute to efforts to mitigate disease.

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Sexton, Danielle L., Francesca A. Herlihey, Ashley S. Brott, David A. Crisante, Evan Shepherdson, Anthony J. Clarke, and Marie A. Elliot. "Roles of LysM and LytM domains in resuscitation-promoting factor (Rpf) activity and Rpf-mediated peptidoglycan cleavage and dormant spore reactivation." Journal of Biological Chemistry 295, no. 27 (May 20, 2020): 9171–82. http://dx.doi.org/10.1074/jbc.ra120.013994.

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Bacterial dormancy can take many forms, including formation of Bacillus endospores, Streptomyces exospores, and metabolically latent Mycobacterium cells. In the actinobacteria, including the streptomycetes and mycobacteria, the rapid resuscitation from a dormant state requires the activities of a family of cell-wall lytic enzymes called resuscitation-promoting factors (Rpfs). Whether Rpf activity promotes resuscitation by generating peptidoglycan fragments (muropeptides) that function as signaling molecules for spore germination or by simply remodeling the dormant cell wall has been the subject of much debate. Here, to address this question, we used mutagenesis and peptidoglycan binding and cleavage assays to first gain broader insight into the biochemical function of diverse Rpf enzymes. We show that their LysM and LytM domains enhance Rpf enzyme activity; their LytM domain and, in some cases their LysM domain, also promoted peptidoglycan binding. We further demonstrate that the Rpfs function as endo-acting lytic transglycosylases, cleaving within the peptidoglycan backbone. We also found that unlike in other systems, Rpf activity in the streptomycetes is not correlated with peptidoglycan-responsive Ser/Thr kinases for cell signaling, and the germination of rpf mutant strains could not be stimulated by the addition of known germinants. Collectively, these results suggest that in Streptomyces, Rpfs have a structural rather than signaling function during spore germination, and that in the actinobacteria, any signaling function associated with spore resuscitation requires the activity of additional yet to be identified enzymes.

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Mahajan, Mayank, Christian Seeger, Benjamin Yee, and Siv G. E. Andersson. "Evolutionary Remodeling of the Cell Envelope in Bacteria of the Planctomycetes Phylum." Genome Biology and Evolution 12, no. 9 (August 6, 2020): 1528–48. http://dx.doi.org/10.1093/gbe/evaa159.

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Abstract Bacteria of the Planctomycetes phylum have many unique cellular features, such as extensive membrane invaginations and the ability to import macromolecules. These features raise intriguing questions about the composition of their cell envelopes. In this study, we have used microscopy, phylogenomics, and proteomics to examine the composition and evolution of cell envelope proteins in Tuwongella immobilis and other members of the Planctomycetes. Cryo-electron tomography data indicated a distance of 45 nm between the inner and outer membranes in T. immobilis. Consistent with the wide periplasmic space, our bioinformatics studies showed that the periplasmic segments of outer-membrane proteins in type II secretion systems are extended in bacteria of the order Planctomycetales. Homologs of two highly abundant cysteine-rich cell wall proteins in T. immobilis were identified in all members of the Planctomycetales, whereas genes for peptidoglycan biosynthesis and cell elongation have been lost in many members of this bacterial group. The cell wall proteins contain multiple copies of the YTV motif, which is the only domain that is conserved and unique to the Planctomycetales. Earlier diverging taxa in the Planctomycetes phylum contain genes for peptidoglycan biosynthesis but no homologs to the YTV cell wall proteins. The major remodeling of the cell envelope in the ancestor of the Planctomycetales coincided with the emergence of budding and other unique cellular phenotypes. The results have implications for hypotheses about the process whereby complex cellular features evolve in bacteria.

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Videau, Patrick, Orion S. Rivers, Blake Ushijima, Reid T. Oshiro, Min Joo Kim, Benjamin Philmus, and Loralyn M. Cozy. "Mutation of themurCandmurBGenes Impairs Heterocyst Differentiation in Anabaena sp. Strain PCC 7120." Journal of Bacteriology 198, no. 8 (January 25, 2016): 1196–206. http://dx.doi.org/10.1128/jb.01027-15.

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ABSTRACTTo stabilize cellular integrity in the face of environmental perturbations, most bacteria, including cyanobacteria, synthesize and maintain a strong, flexible, three-dimensional peptidoglycan lattice.Anabaenasp. strain PCC 7120 is a filamentous cyanobacterium capable of differentiating morphologically distinct nitrogen-fixing heterocyst cells in a periodic pattern. While heterocyst development has been shown to require proper peptidoglycan remodeling, the role of peptidoglycan synthesis has remained unclear. Here we report the identification of two peptidoglycan synthesis genes,murC(alr5065) andmurB(alr5066), as required for heterocyst development. ThemurCandmurBgenes are predicted to encode a UDP-N-acetylmuramate:l-alanine ligase and a UDP-N-acetylenolpyruvoylglucosamine reductase, respectively, and we confirm enzymatic function through complementation ofEscherichia colistrains deficient for these enzymes. Cells depleted of eithermurCormurBexpression failed to differentiate heterocysts under normally inducing conditions and displayed decreased filament integrity. To identify the stage(s) of development affected bymurCormurBdepletion, the spatial distribution of expression of the patterning marker gene,patS, was examined. WhereasmurBdepletion did not affect the pattern ofpatSexpression,murCdepletion led to aberrant expression ofpatSin all cells of the filament. Finally, expression ofgfpcontrolled by the region of DNA immediately upstream ofmurCwas enriched in differentiating cells and was repressed by the transcription factor NtcA. Collectively, the data in this work provide evidence for a direct link between peptidoglycan synthesis and the maintenance of a biological pattern in a multicellular organism.IMPORTANCEMulticellular organisms that differentiate specialized cells must regulate morphological changes such that both cellular integrity and the dissemination of developmental signals are preserved. Here we show that the multicellular bacteriumAnabaena, which differentiates a periodic pattern of specialized heterocyst cells, requires peptidoglycan synthesis by the murine ligase genesmurC(alr5065) andmurB(alr5066) for maintenance of patterned gene expression, filament integrity, and overall development. This work highlights the significant influence that intracellular structure and intercellular connections can have on the execution of a developmental program.

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Apostolos, Alexis J., Sean E. Pidgeon, and Marcos M. Pires. "Remodeling of Cross-bridges Controls Peptidoglycan Cross-linking Levels in Bacterial Cell Walls." ACS Chemical Biology 15, no. 5 (March 13, 2020): 1261–67. http://dx.doi.org/10.1021/acschembio.0c00002.

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Oliveira, Amanda C. P., Rafael M. Ferreira, Maria Inês T. Ferro, Jesus A. Ferro, Mick Chandler, and Alessandro M. Varani. "Transposons and pathogenicity inXanthomonas: acquisition of murein lytic transglycosylases by TnXax1enhancesXanthomonas citrisubsp.citri306 virulence and fitness." PeerJ 6 (December 19, 2018): e6111. http://dx.doi.org/10.7717/peerj.6111.

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Xanthomonas citrisubsp.citri306 (XccA) is the causal agent of type A citrus canker (CC), one of the most significant citriculture diseases. Murein lytic transglycosylases (LT), potentially involved in XccA pathogenicity, are enzymes responsible for peptidoglycan structure assembly, remodeling and degradation. They directly impact cell wall expansion during bacterial growth, septum division allowing cell separation, cell wall remodeling allowing flagellar assembly, bacterial conjugation, muropeptide recycling, and secretion system assembly, in particular the Type 3 Secretion System involved in bacterial virulence, which play a fundamental role in XccA pathogenicity. Information about the XccA LT arsenal is patchy: little is known about family diversity, their exact role or their connection to virulence in this bacterium. Among the LTs with possible involvement in virulence, two paralogue open reading frames (ORFs) (one on the chromosome and one in plasmid pXAC64) are passenger genes of the Tn3family transposon TnXax1, known to play a significant role in the evolution and emergence of pathogenicity inXanthomonadalesand to carry a variety of virulence determinants. This study addresses LT diversity in the XccA genome and examines the role of plasmid and chromosomal TnXax1LT passenger genes using site-directed deletion mutagenesis and functional characterization. We identified 13 XccA LTs: 12 belong to families 1A, 1B, 1C, 1D (two copies), 1F, 1G, 3A, 3B (two copies), 5A, 6A and one which is non-categorized. The non-categorized LT is exclusive to theXanthomonasgenus and related to the 3B family but contains an additional domain linked to carbohydrate metabolism. The categorized LTs are probably involved in cell wall remodeling to allow insertion of type 3, 4 and 6 secretion systems, flagellum assembly, division and recycling of cell wall and degradation and control of peptidoglycan production. The TnXax1passenger LT genes (3B family) are not essential to XccA or for CC development but are implicated in peptidoglycan metabolism, directly impacting bacterial fitness and CC symptom enhancement in susceptible hosts (e.g.,Citrus sinensis). This underlines the role of TnXax1as a virulence and pathogenicity-propagating agent in XccA and suggests that LT acquisition by horizontal gene transfer mediated by TnXax1may improve bacterial fitness, conferring adaptive advantages to the plant-pathogen interaction process.

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Takacs, Constantin N., Sebastian Poggio, Godefroid Charbon, Mathieu Pucheault, Waldemar Vollmer, and Christine Jacobs-Wagner. "MreB Drives De Novo Rod Morphogenesis in Caulobacter crescentus via Remodeling of the Cell Wall." Journal of Bacteriology 192, no. 6 (December 18, 2009): 1671–84. http://dx.doi.org/10.1128/jb.01311-09.

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ABSTRACT MreB, the bacterial actin-like cytoskeleton, is required for the rod morphology of many bacterial species. Disruption of MreB function results in loss of rod morphology and cell rounding. Here, we show that the widely used MreB inhibitor A22 causes MreB-independent growth inhibition that varies with the drug concentration, culture medium conditions, and bacterial species tested. MP265, an A22 structural analog, is less toxic than A22 for growth yet equally efficient for disrupting the MreB cytoskeleton. The action of A22 and MP265 is enhanced by basic pH of the culture medium. Using this knowledge and the rapid reversibility of drug action, we examined the restoration of rod shape in lemon-shaped Caulobacter crescentus cells pretreated with MP265 or A22 under nontoxic conditions. We found that reversible restoration of MreB function after drug removal causes extensive morphological changes including a remarkable cell thinning accompanied with elongation, cell branching, and shedding of outer membrane vesicles. We also thoroughly characterized the composition of C. crescentus peptidoglycan by high-performance liquid chromatography and mass spectrometry and showed that MreB disruption and recovery of rod shape following restoration of MreB function are accompanied by considerable changes in composition. Our results provide insight into MreB function in peptidoglycan remodeling and rod shape morphogenesis and suggest that MreB promotes the transglycosylase activity of penicillin-binding proteins.

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Cavallari, Joseph F., Ryan P. Lamers, Edie M. Scheurwater, Andrea L. Matos, and Lori L. Burrows. "Changes to Its Peptidoglycan-Remodeling Enzyme Repertoire Modulate β-Lactam Resistance in Pseudomonas aeruginosa." Antimicrobial Agents and Chemotherapy 57, no. 7 (April 22, 2013): 3078–84. http://dx.doi.org/10.1128/aac.00268-13.

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ABSTRACTPseudomonas aeruginosais a leading cause of hospital-acquired infections and is resistant to many antibiotics. Among its primary mechanisms of resistance is expression of a chromosomally encoded AmpC β-lactamase that inactivates β-lactams. The mechanisms leading to AmpC expression inP. aeruginosaremain incompletely understood but are intricately linked to cell wall metabolism. To better understand the roles of peptidoglycan-active enzymes in AmpC expression—and consequent β-lactam resistance—a phenotypic screen ofP. aeruginosamutants lacking such enzymes was performed. Mutants lacking one of four lytic transglycosylases (LTs) or the nonessential penicillin-binding protein PBP4 (dacB) had altered β-lactam resistance.mltFandsltmutants with reduced β-lactam resistance were designated WIMPs (wall-impaired mutant phenotypes), while highly resistantdacB,sltB1, andmltBmutants were designated HARMs (high-level AmpC resistant mutants). Double mutants lackingdacBandsltB1had extreme piperacillin resistance (>256 μg/ml) compared to either of the single knockouts (64 μg/ml for adacBmutant and 12 μg/ml for ansltB1mutant). Inactivation ofampCreverted these mutants to wild-type susceptibility, confirming that AmpC expression underlies resistance.dacBmutants had constitutively elevated AmpC expression, but the LT mutants had wild-type levels of AmpC in the absence of antibiotic exposure. These data suggest that there are at least two different pathways leading to AmpC expression inP. aeruginosaand that their simultaneous activation leads to extreme β-lactam resistance.

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Fura, Jonathan M., and Marcos M. Pires. "d-amino carboxamide-based recruitment of dinitrophenol antibodies to bacterial surfaces via peptidoglycan remodeling." Biopolymers 104, no. 4 (July 2015): 351–59. http://dx.doi.org/10.1002/bip.22618.

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Tocheva, Elitza I., Eric G. Matson, Dylan M. Morris, Farshid Moussavi, Jared R. Leadbetter, and Grant J. Jensen. "Peptidoglycan Remodeling and Conversion of an Inner Membrane into an Outer Membrane during Sporulation." Cell 146, no. 5 (September 2011): 799–812. http://dx.doi.org/10.1016/j.cell.2011.07.029.

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Böth, Dominic, Gunter Schneider, and Robert Schnell. "Peptidoglycan Remodeling in Mycobacterium tuberculosis: Comparison of Structures and Catalytic Activities of RipA and RipB." Journal of Molecular Biology 413, no. 1 (October 2011): 247–60. http://dx.doi.org/10.1016/j.jmb.2011.08.014.

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Yakhnina, Anastasiya A., and Thomas G. Bernhardt. "The Tol-Pal system is required for peptidoglycan-cleaving enzymes to complete bacterial cell division." Proceedings of the National Academy of Sciences 117, no. 12 (March 9, 2020): 6777–83. http://dx.doi.org/10.1073/pnas.1919267117.

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Tol-Pal is a multiprotein system present in the envelope of Gram-negative bacteria. Inactivation of this widely conserved machinery compromises the outer membrane (OM) layer of these organisms, resulting in hypersensitivity to many antibiotics. Mutants in thetol-pallocus fail to complete division and form cell chains. This phenotype along with the localization of Tol-Pal components to the cytokinetic ring inEscherichia colihas led to the proposal that the primary function of the system is to promote OM constriction during division. Accordingly, a poorly constricted OM is believed to link the cell chains formed upon Tol-Pal inactivation. However, we show here that cell chains ofE. coli tol-palmutants are connected by an incompletely processed peptidoglycan (PG) layer. Genetic suppressors of this defect were isolated and found to overproduce OM lipoproteins capable of cleaving the glycan strands of PG. Among the factors promoting cell separation in mutant cells was a protein of previously unknown function (YddW), which we have identified as a divisome-localized glycosyl hydrolase that cleaves peptide-free PG glycans. Overall, our results indicate that the cell chaining defect of Tol-Pal mutants cannot simply be interpreted as a defect in OM constriction. Rather, the complex also appears to be required for the activity of several OM-localized enzymes with cell wall remodeling activity. Thus, the Tol-Pal system may play a more general role in coordinating OM invagination with PG remodeling at the division site than previously appreciated.

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Sigle, Steffen, Nadja Steblau, Wolfgang Wohlleben, and Günther Muth. "Polydiglycosylphosphate Transferase PdtA (SCO2578) of Streptomyces coelicolor A3(2) Is Crucial for Proper Sporulation and Apical Tip Extension under Stress Conditions." Applied and Environmental Microbiology 82, no. 18 (July 15, 2016): 5661–72. http://dx.doi.org/10.1128/aem.01425-16.

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ABSTRACTAlthough anionic glycopolymers are crucial components of the Gram-positive cell envelope, the relevance of anionic glycopolymers for vegetative growth and morphological differentiation ofStreptomyces coelicolorA3(2) is unknown. Here, we show that the LytR-CpsA-Psr (LCP) protein PdtA (SCO2578), a TagV-like glycopolymer transferase, has a dual function in theS. coelicolorA3(2) life cycle. Despite the presence of 10 additional LCP homologs, PdtA is crucial for proper sporulation. The integrity of the spore envelope was severely affected in apdtAdeletion mutant, resulting in 34% nonviable spores.pdtAdeletion caused a significant reduction in the polydiglycosylphosphate content of the spore envelope. Beyond that, apical tip extension and normal branching of vegetative mycelium were severely impaired on high-salt medium. This growth defect coincided with the mislocalization of peptidoglycan synthesis. Thus, PdtA itself or the polydiglycosylphosphate attached to the peptidoglycan by the glycopolymer transferase PdtA also has a crucial function in apical tip extension of vegetative hyphae under stress conditions.IMPORTANCEAnionic glycopolymers are underappreciated components of the Gram-positive cell envelope. They provide rigidity to the cell wall and position extracellular enzymes involved in peptidoglycan remodeling. AlthoughStreptomyces coelicolorA3(2), the model organism for bacterial antibiotic production, is known to produce two distinct cell wall-linked glycopolymers, teichulosonic acid and polydiglycosylphosphate, the role of these glycopolymers in theS. coelicolorA3(2) life cycle has not been addressed so far. This study reveals a crucial function of the anionic glycopolymer polydiglycosylphosphate for the growth and morphological differentiation ofS. coelicolorA3(2). Polydiglycosylphosphate is attached to the spore wall by the LytR-CpsA-Psr protein PdtA (SCO2578), a component of theStreptomycesspore wall-synthesizing complex (SSSC), to ensure the integrity of the spore envelope. Surprisingly, PdtA also has a crucial role in vegetative growth under stress conditions and is required for proper peptidoglycan incorporation during apical tip extension.

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Hervé, Mireille, Audrey Boniface, Stanislav Gobec, Didier Blanot, and Dominique Mengin-Lecreulx. "Biochemical Characterization and Physiological Properties of Escherichia coli UDP-N-Acetylmuramate:l-Alanyl-γ-d-Glutamyl-meso- Diaminopimelate Ligase." Journal of Bacteriology 189, no. 11 (March 23, 2007): 3987–95. http://dx.doi.org/10.1128/jb.00087-07.

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ABSTRACT The UDP-N-acetylmuramate:l-alanyl-γ-d-glutamyl-meso-diaminopimelate ligase (murein peptide ligase [Mpl]) is known to be a recycling enzyme allowing reincorporation into peptidoglycan (murein) of the tripeptide l-alanyl-γ-d-glutamyl-meso-diaminopimelate released during the maturation and constant remodeling of this bacterial cell wall polymer that occur during cell growth and division. Mpl adds this peptide to UDP-N-acetylmuramic acid, thereby providing an economical additional source of UDP-MurNAc-tripeptide available for de novo peptidoglycan biosynthesis. The Mpl enzyme from Escherichia coli was purified to homogeneity as a His-tagged form, and its kinetic properties and parameters were determined. Mpl was found to accept tri-, tetra-, and pentapeptides as substrates in vitro with similar efficiencies, but it accepted the dipeptide l-Ala-d-Glu and l-Ala very poorly. Replacement of meso-diaminopimelic acid by l-Lys resulted in a significant decrease in the catalytic efficacy. The effects of disruption of the E. coli mpl gene and/or the ldcA gene encoding the ld-carboxypeptidase on peptidoglycan metabolism were investigated. The differences in the pools of UDP-MurNAc peptides and of free peptides between the wild-type and mutant strains demonstrated that the recycling activity of Mpl is not restricted to the tripeptide and that tetra- and pentapeptides are also directly reused by this process in vivo. The relatively broad substrate specificity of the Mpl ligase indicates that it is an interesting potential target for antibacterial compounds.

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Sexton, Danielle L., Renée J. St-Onge, Henry J. Haiser, Mary R. Yousef, Lauren Brady, Chan Gao, Jacqueline Leonard, and Marie A. Elliot. "Resuscitation-Promoting Factors Are Cell Wall-Lytic Enzymes with Important Roles in the Germination and Growth of Streptomyces coelicolor." Journal of Bacteriology 197, no. 5 (December 15, 2014): 848–60. http://dx.doi.org/10.1128/jb.02464-14.

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Dormancy is a common strategy adopted by bacterial cells as a means of surviving adverse environmental conditions. ForStreptomycesbacteria, this involves developing chains of dormant exospores that extend away from the colony surface. Both spore formation and subsequent spore germination are tightly controlled processes, and while significant progress has been made in understanding the underlying regulatory and enzymatic bases for these, there are still significant gaps in our understanding. One class of proteins with a potential role in spore-associated processes are the so-called resuscitation-promoting factors, or Rpfs, which in other actinobacteria are needed to restore active growth to dormant cell populations. The model speciesStreptomyces coelicolorencodes five Rpf proteins (RpfA to RfpE), and here we show that these proteins have overlapping functions during growth. Collectively, theS. coelicolorRpfs promote spore germination and are critical for growth under nutrient-limiting conditions. Previous studies have revealed structural similarities between the Rpf domain and lysozyme, and ourin vitrobiochemical assays revealed various levels of peptidoglycan cleavage capabilities for each of these fiveStreptomycesenzymes. Peptidoglycan remodeling by enzymes such as these must be stringently governed so as to retain the structural integrity of the cell wall. Our results suggest that one of the Rpfs, RpfB, is subject to a unique mode of enzymatic autoregulation, mediated by a domain of previously unknown function (DUF348) located within the N terminus of the protein; removal of this domain led to significantly enhanced peptidoglycan cleavage.

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Bai, Xiao-Hui, Hui-Jie Chen, Yong-Liang Jiang, Zhensong Wen, Yubin Huang, Wang Cheng, Qiong Li, et al. "Structure of Pneumococcal Peptidoglycan Hydrolase LytB Reveals Insights into the Bacterial Cell Wall Remodeling and Pathogenesis." Journal of Biological Chemistry 289, no. 34 (July 7, 2014): 23403–16. http://dx.doi.org/10.1074/jbc.m114.579714.

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Schaub, Ryan E., Yolande A. Chan, Mijoon Lee, Dusan Hesek, Shahriar Mobashery, and Joseph P. Dillard. "Lytic transglycosylases LtgA and LtgD perform distinct roles in remodeling, recycling and releasing peptidoglycan inNeisseria gonorrhoeae." Molecular Microbiology 102, no. 5 (September 26, 2016): 865–81. http://dx.doi.org/10.1111/mmi.13496.

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Goffin, Colette, and Jean-Marie Ghuysen. "Biochemistry and Comparative Genomics of SxxK Superfamily Acyltransferases Offer a Clue to the Mycobacterial Paradox: Presence of Penicillin-Susceptible Target Proteins versus Lack of Efficiency of Penicillin as Therapeutic Agent." Microbiology and Molecular Biology Reviews 66, no. 4 (December 2002): 702–38. http://dx.doi.org/10.1128/mmbr.66.4.702-738.2002.

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SUMMARY The bacterial acyltransferases of the SxxK superfamily vary enormously in sequence and function, with conservation of particular amino acid groups and all-α and α/β folds. They occur as independent entities (free-standing polypeptides) and as modules linked to other polypeptides (protein fusions). They can be classified into three groups. The group I SxxK d,d-acyltransferases are ubiquitous in the bacterial world. They invariably bear the motifs SxxK, SxN(D), and KT(S)G. Anchored in the plasma membrane with the bulk of the polypeptide chain exposed on the outer face of it, they are implicated in the synthesis of wall peptidoglycans of the most frequently encountered (4→3) type. They are inactivated by penicillin and other β-lactam antibiotics acting as suicide carbonyl donors in the form of penicillin-binding proteins (PBPs). They are components of a morphogenetic apparatus which, as a whole, controls multiple parameters such as shape and size and allows the bacterial cells to enlarge and duplicate their particular pattern. Class A PBP fusions comprise a glycosyltransferase module fused to an SxxK acyltransferase of class A. Class B PBP fusions comprise a linker, i.e., protein recognition, module fused to an SxxK acyltransferase of class B. They ensure the remodeling of the (4→3) peptidoglycans in a cell cycle-dependent manner. The free-standing PBPs hydrolyze d,d peptide bonds. The group II SxxK acyltransferases frequently have a partially modified bar code, but the SxxK motif is invariant. They react with penicillin in various ways and illustrate the great plasticity of the catalytic centers. The secreted free-standing PBPs, the serine β-lactamases, and the penicillin sensors of several penicillin sensory transducers help the d,d-acyltransferases of group I escape penicillin action. The group III SxxK acyltransferases are indistinguishable from the PBP fusion proteins of group I in motifs and membrane topology, but they resist penicillin. They are referred to as Penr protein fusions. Plausible hypotheses are put forward on the roles that the Penr protein fusions, acting as l,d-acyltransferases, may play in the (3→3) peptidoglycan-synthesizing molecular machines. Shifting the wall peptidoglycan from the (4→3) type to the (3→3) type could help Mycobacterium tuberculosis and Mycobacterium leprae survive by making them penicillin resistant.

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Osawa, Masaki, and Harold P. Erickson. "FtsZ from Divergent Foreign Bacteria Can Function for Cell Division in Escherichia coli." Journal of Bacteriology 188, no. 20 (October 1, 2006): 7132–40. http://dx.doi.org/10.1128/jb.00647-06.

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ABSTRACT FtsZs from Mycoplasma pulmonis (MpuFtsZ) and Bacillus subtilis (BsFtsZ) are only 46% and 53% identical in amino acid sequence to FtsZ from Escherichia coli (EcFtsZ). In the present study we show that MpuFtsZ and BsFtsZ can function for cell division in E. coli provided we make two modifications. First, we replaced their C-terminal tails with that from E. coli, giving the foreign FtsZ the binding site for E. coli FtsA and ZipA. Second, we selected for mutations in the E. coli genome that facilitated division by the foreign FtsZs. These suppressor strains arose at a relatively high frequency of 10−3 to 10−5, suggesting that they involve loss-of-function mutations in multigene pathways. These pathways may be negative regulators of FtsZ or structural pathways that facilitate division by slightly defective FtsZ. Related suppressor strains were obtained for EcFtsZ containing certain point mutations or insertions of yellow fluorescent protein. The ability of highly divergent FtsZs to function for division in E. coli is consistent with a two-part mechanism. FtsZ assembles the Z ring, and perhaps generates the constriction force, through self interactions; the downstream division proteins remodel the peptidoglycan wall by interacting with each other and the wall. The C-terminal peptide of FtsZ, which binds FtsA, provides the link between FtsZ assembly and peptidoglycan remodeling.

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Hu, Bo, William Margolin, Ian J. Molineux, and Jun Liu. "Structural remodeling of bacteriophage T4 and host membranes during infection initiation." Proceedings of the National Academy of Sciences 112, no. 35 (August 17, 2015): E4919—E4928. http://dx.doi.org/10.1073/pnas.1501064112.

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The first stages of productive bacteriophage infections of bacterial host cells require efficient adsorption to the cell surface followed by ejection of phage DNA into the host cytoplasm. To achieve this goal, a phage virion must undergo significant structural remodeling. For phage T4, the most obvious change is the contraction of its tail. Here, we use skinnyE. coliminicells as a host, along with cryo-electron tomography and mutant phage virions, to visualize key structural intermediates during initiation of T4 infection. We show for the first time that most long tail fibers are folded back against the tail sheath until irreversible adsorption, a feature compatible with the virion randomly walking across the cell surface to find an optimal site for infection. Our data confirm that tail contraction is triggered by structural changes in the baseplate, as intermediates were found with remodeled baseplates and extended tails. After contraction, the tail tube penetrates the host cell periplasm, pausing while it degrades the peptidoglycan layer. Penetration into the host cytoplasm is accompanied by a dramatic local outward curvature of the cytoplasmic membrane as it fuses with the phage tail tip. The baseplate hub protein gp27 and/or the ejected tape measure protein gp29 likely form the transmembrane channel for viral DNA passage into the cell cytoplasm. Building on the wealth of prior biochemical and structural information, this work provides new molecular insights into the mechanistic pathway of T4 phage infection.

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Lavollay, Marie, Michel Arthur, Martine Fourgeaud, Lionel Dubost, Arul Marie, Nicolas Veziris, Didier Blanot, Laurent Gutmann, and Jean-Luc Mainardi. "The Peptidoglycan of Stationary-Phase Mycobacterium tuberculosis Predominantly Contains Cross-Links Generated by l,d-Transpeptidation." Journal of Bacteriology 190, no. 12 (April 11, 2008): 4360–66. http://dx.doi.org/10.1128/jb.00239-08.

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ABSTRACT Our understanding of the mechanisms used by Mycobacterium tuberculosis to persist in a “dormant” state is essential to the development of therapies effective in sterilizing tissues. Gene expression profiling in model systems has revealed a complex adaptive response thought to endow M. tuberculosis with the capacity to survive several months of combinatorial antibiotic treatment. We show here that this adaptive response may involve remodeling of the peptidoglycan network by substitution of 4→3 cross-links generated by the d,d-transpeptidase activity of penicillin-binding proteins by 3→3 cross-links generated by a transpeptidase of l,d specificity. A candidate gene, previously shown to be upregulated upon nutrient starvation, was found to encode an l,d-transpeptidase active in the formation of 3→3 cross-links. The enzyme, LdtMt1, was inactivated by carbapenems, a class of β-lactam antibiotics that are poorly hydrolyzed by the M. tuberculosis β-lactamases. LdtMt1 and carbapenems may therefore represent a target and a drug family relevant to the eradication of persistent M. tuberculosis.

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Küssau, Tanja, Niël Van Wyk, Matt D. Johansen, Husam M. A. B. Alsarraf, Aymeric Neyret, Claire Hamela, Kasper K. Sørensen, et al. "Functional Characterization of the N-Acetylmuramyl-l-Alanine Amidase, Ami1, from Mycobacterium abscessus." Cells 9, no. 11 (November 4, 2020): 2410. http://dx.doi.org/10.3390/cells9112410.

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Peptidoglycan (PG) is made of a polymer of disaccharides organized as a three-dimensional mesh-like network connected together by peptidic cross-links. PG is a dynamic structure that is essential for resistance to environmental stressors. Remodeling of PG occurs throughout the bacterial life cycle, particularly during bacterial division and separation into daughter cells. Numerous autolysins with various substrate specificities participate in PG remodeling. Expression of these enzymes must be tightly regulated, as an excess of hydrolytic activity can be detrimental for the bacteria. In non-tuberculous mycobacteria such as Mycobacterium abscessus, the function of PG-modifying enzymes has been poorly investigated. In this study, we characterized the function of the PG amidase, Ami1 from M. abscessus. An ami1 deletion mutant was generated and the phenotypes of the mutant were evaluated with respect to susceptibility to antibiotics and virulence in human macrophages and zebrafish. The capacity of purified Ami1 to hydrolyze muramyl-dipeptide was demonstrated in vitro. In addition, the screening of a 9200 compounds library led to the selection of three compounds inhibiting Ami1 in vitro. We also report the structural characterization of Ami1 which, combined with in silico docking studies, allows us to propose a mode of action for these inhibitors.

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Haiser, Henry J., Mary R. Yousef, and Marie A. Elliot. "Cell Wall Hydrolases Affect Germination, Vegetative Growth, and Sporulation in Streptomyces coelicolor." Journal of Bacteriology 191, no. 21 (August 28, 2009): 6501–12. http://dx.doi.org/10.1128/jb.00767-09.

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ABSTRACT Peptidoglycan is a major cell wall constituent of gram-positive bacteria. It is a dynamic macromolecule that is actively remodeled to enable cell growth and differentiation through a tightly choreographed interplay of hydrolytic and biosynthetic enzyme activities. The filamentous bacterium Streptomyces coelicolor has a complex life cycle that likely requires considerable cell wall remodeling to enable both extension of vegetative hyphae and formation of differentiated cell types. In silico analysis of the S. coelicolor genome enabled identification of 56 candidate cell wall hydrolase genes. We found that seven of these genes shared a highly conserved 5′ untranslated region and were expressed during both vegetative growth and sporulation; four of these genes were selected for more extensive biochemical and biological characterization. The proteins encoded by these genes, termed RpfA, SwlA, SwlB, and SwlC, were confirmed to be hydrolytic enzymes, as they could efficiently cleave S. coelicolor cell walls. Phenotypic analyses revealed that these enzymes are important throughout development; deletion of each hydrolase gene resulted in a mutant strain that was heat sensitive, defective in spore formation, and either altered in vegetative growth or delayed in spore germination. Our results indicate that these enzymes play key roles at multiple stages in the growth and development of S. coelicolor, highlighting both the lack of redundancy in hydrolase activity and the importance of cell wall remodeling in the S. coelicolor life cycle.

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Shen, Lin, Albertus Viljoen, Sydney Villaume, Maju Joe, Iman Halloum, Loïc Chêne, Alexandre Méry, et al. "The endogenous galactofuranosidase GlfH1 hydrolyzes mycobacterial arabinogalactan." Journal of Biological Chemistry 295, no. 15 (February 27, 2020): 5110–23. http://dx.doi.org/10.1074/jbc.ra119.011817.

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Despite impressive progress made over the past 20 years in our understanding of mycolylarabinogalactan-peptidoglycan (mAGP) biogenesis, the mechanisms by which the tubercle bacillus Mycobacterium tuberculosis adapts its cell wall structure and composition to various environmental conditions, especially during infection, remain poorly understood. Being the central portion of the mAGP complex, arabinogalactan (AG) is believed to be the constituent of the mycobacterial cell envelope that undergoes the least structural changes, but no reports exist supporting this assumption. Herein, using recombinantly expressed mycobacterial protein, bioinformatics analyses, and kinetic and biochemical assays, we demonstrate that the AG can be remodeled by a mycobacterial endogenous enzyme. In particular, we found that the mycobacterial GlfH1 (Rv3096) protein exhibits exo-β-d-galactofuranose hydrolase activity and is capable of hydrolyzing the galactan chain of AG by recurrent cleavage of the terminal β-(1,5) and β-(1,6)-Galf linkages. The characterization of this galactosidase represents a first step toward understanding the remodeling of mycobacterial AG.

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Chen, Rui, Sarah B. Guttenplan, Kris M. Blair, and Daniel B. Kearns. "Role of the σD-Dependent Autolysins in Bacillus subtilis Population Heterogeneity." Journal of Bacteriology 191, no. 18 (June 19, 2008): 5775–84. http://dx.doi.org/10.1128/jb.00521-09.

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ABSTRACT Exponentially growing populations of Bacillus subtilis contain two morphologically and functionally distinct cell types: motile individuals and nonmotile multicellular chains. Motility differentiation arises because RNA polymerase and the alternative sigma factor σD activate expression of flagellin in a subpopulation of cells. Here we demonstrate that the peptidoglycan-remodeling autolysins under σD control, LytC, LytD, and LytF, are expressed in the same subpopulation of cells that complete flagellar synthesis. Morphological heterogeneity is explained by the expression of LytF that is necessary and sufficient for cell separation. Moreover, LytC is required for motility but not at the level of cell separation or flagellum biosynthesis. Rather, LytC appears to be important for flagellar function, and motility was restored to a LytC mutant by mutation of either lonA, encoding the LonA protease, or a gene encoding a previously unannotated swarming motility inhibitor, SmiA. We conclude that heterogeneous activation of σD-dependent gene expression is sufficient to explain both the morphological heterogeneity and functional heterogeneity present in vegetative B. subtilis populations.

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Bernal-Cabas, Margarita, Juan Alfonso Ayala, and Tracy L. Raivio. "The Cpx Envelope Stress Response Modifies Peptidoglycan Cross-Linking via the l,d-Transpeptidase LdtD and the Novel Protein YgaU." Journal of Bacteriology 197, no. 3 (November 24, 2014): 603–14. http://dx.doi.org/10.1128/jb.02449-14.

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The Cpx envelope stress response mediates a complex adaptation to conditions that cause protein misfolding in the periplasm. A recent microarray study demonstrated that Cpx response activation led to changes in the expression of genes known, or predicted, to be involved in cell wall remodeling. We sought to characterize the changes that the cell wall undergoes during activation of the Cpx pathway inEscherichia coli. Luminescent reporters of gene expression confirmed that LdtD, a putativel,d-transpeptidase; YgaU, a protein of unknown function; and Slt, a lytic transglycosylase, are upregulated in response to Cpx-inducing conditions. Phosphorylated CpxR binds to the upstream regions of these genes, which contain putative CpxR binding sites, suggesting that regulation is direct. We show that the activation of the Cpx response causes an increase in the abundance of diaminopimelic acid (DAP)-DAP cross-links that involves LdtD and YgaU. Altogether, our data indicate that changes in peptidoglycan structure are part of the Cpx-mediated adaptation to envelope stress and indicate a role for the uncharacterized geneygaUin regulating cross-linking.

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Langro, Justin M., Megan M. Chamberland, Celena M. Gwin, Natalia Prakash, Danielle T. Velez, and Nathan W. Rigel. "TatC2 is Important for Growth of Acinetobacter baylyi Under Stress Conditions." Fine Focus 5, no. 1 (October 16, 2019): 37–50. http://dx.doi.org/10.33043/ff.5.1.37-50.

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Protein export pathways are important for bacterial physiology among pathogens and non-pathogens alike. This includes the Twin-Arginine Translocation (Tat) pathway, which transports fully folded proteins across the bacterial cytoplasmic membrane. Some Tat substrates are virulence factors, while others are important for cellular processes like peptidoglycan remodeling. Some bacteria encode more than one copy of each Tat component, including the Gram-negative soil isolate Acinetobacter baylyi. One of these Tat pathways is essential for growth, while the other is not. We constructed a loss-of-function mutation to disrupt the non-essential tatC2 gene and assessed its contribution to cell growth under different environmental conditions. While the tatC2 mutant grew well under standard laboratory conditions, it displayed a growth defect and an aberrant cellular morphology when subjected to high temperature stress including an aberrant cellular morphology. Furthermore, increased sensitivities to detergent suggested a compromised cell envelope. Lastly, using an in vitro co-culture system, we demonstrate that the non-essential Tat pathway provides a growth advantage. The findings of this study establish the importance of the non-essential Tat pathway for optimal growth of A. baylyi in stressful environmental conditions.

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Jurynec, Michael J., Allen D. Sawitzke, Timothy C. Beals, Michael J. Redd, Jeff Stevens, Brith Otterud, Mark F. Leppert, and David Jonah Grunwald. "A hyperactivating proinflammatory RIPK2 allele associated with early-onset osteoarthritis." Human Molecular Genetics 27, no. 13 (April 12, 2018): 2383–91. http://dx.doi.org/10.1093/hmg/ddy132.

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Abstract Osteoarthritis (OA) is a common debilitating disease characterized by abnormal remodeling of the cartilage and bone of the articular joint. Ameliorating therapeutics are lacking due to limited understanding of the molecular pathways affecting disease initiation and progression. Notably, although a link between inflammation and overt OA is well established, the role of inflammation as a driver of disease occurrence is highly disputed. We analyzed a family with dominant inheritance of early-onset OA and found that affected individuals harbored a rare variant allele encoding a significant amino acid change (p.Asn104Asp) in the kinase domain of receptor interacting protein kinase 2 (RIPK2), which transduces signals from activated bacterial peptidoglycan sensors through the NF-κB pathway to generate a proinflammatory immune response. Functional analyses of RIPK2 activity in zebrafish embryos indicated that the variant RIPK2104Asp protein is hyperactive in its signaling capacity, with augmented ability to activate the innate immune response and the NF-κB pathway and to promote upregulation of OA-associated genes. Further we show a second allele of RIPK2 linked to an inflammatory disease associated with arthritis also has enhanced activity stimulating the NF-κB pathway. Our studies reveal for the first time the inflammatory response can function as a gatekeeper risk factor for OA.

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Crunkhorn, Sarah. "Inhibiting peptidoglycan remodelling." Nature Reviews Drug Discovery 19, no. 4 (March 9, 2020): 238. http://dx.doi.org/10.1038/d41573-020-00035-x.

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Hill, Craig M., Kevin M. Krause, Stacey R. Lewis, Johanne Blais, Bret M. Benton, Mathai Mammen, Patrick P. Humphrey, Alfred Kinana, and James W. Janc. "Specificity of Induction of the vanA and vanB Operons in Vancomycin-Resistant Enterococci by Telavancin." Antimicrobial Agents and Chemotherapy 54, no. 7 (April 19, 2010): 2814–18. http://dx.doi.org/10.1128/aac.01737-09.

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ABSTRACT Telavancin is a bactericidal, semisynthetic lipoglycopeptide indicated in the United States for the treatment of complicated skin and skin structure infections caused by susceptible Gram-positive bacteria and is under investigation as a once-daily treatment for nosocomial pneumonia. The related vanA and vanB gene clusters mediate acquired resistance to glycopeptides in enterococci by remodeling the dipeptide termini of peptidoglycan precursors from d-alanyl-d-alanine (d-Ala-d-Ala) to d-alanyl-d-lactate (d-Ala-d-Lac). In this study, we assessed the ability of telavancin to induce the expression of van genes in VanA- and VanB-type strains of vancomycin-resistant enterococci. Vancomycin, teicoplanin, and telavancin efficiently induced VanX activity in VanA-type strains, while VanX activity in VanB-type isolates was inducible by vancomycin but not by teicoplanin or telavancin. In VanA-type strains treated with vancomycin or telavancin, high levels of d-Ala-d-Lac-containing pentadepsipeptide were measured, while d-Ala-d-Ala pentapeptide was present at very low levels or not detected at all. In VanB-type strains, vancomycin but not telavancin induced high levels of pentadepsipeptide, while pentapeptide was not detected. Although vancomycin, teicoplanin, and telavancin induced similar levels of VanX activity in VanA-type strains, these organisms were more sensitive to telavancin, which displayed MIC values that were 32- and 128-fold lower than those of vancomycin and teicoplanin, respectively.

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Lu, Peng-Yuan, Guo-Juan Niu, Pan-Pan Hong, and Jin-Xing Wang. "Lysyl Oxidase-like Protein Recognizes Viral Envelope Proteins and Bacterial Polysaccharides against Pathogen Infection via Induction of Expression of Antimicrobial Peptides." Viruses 14, no. 9 (September 18, 2022): 2072. http://dx.doi.org/10.3390/v14092072.

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Lysyl oxidases (LOXs) are copper-dependent monoamine oxidases, and they play critical roles in extracellular matrix (ECM) remodeling. The LOX and LOX-like (LOXL) proteins also have a variety of biological functions, such as development and growth regulation, tumor suppression, and cellular senescence. However, the functions of LOXLs containing repeated scavenger receptor cysteine-rich (SRCR) domains in immunity are rarely reported. In this study, we characterized the antiviral and antibacterial functions of a lysyl oxidase-like (LOXL) protein containing tandem SRCR domains in Marsupenaeus japonicus. The mRNA level of LoxL was significantly upregulated in the hemocytes and intestines of shrimp challenged using white spot syndrome virus (WSSV) or bacteria. After the knockdown of LoxL via RNA interference, WSSV replication and bacterial loads were apparently increased, and the survival rate of the shrimp decreased significantly, suggesting that LOXL functions against pathogen infection in shrimp. Mechanistically, LOXL interacted with the envelope proteins of WSSV or with lipopolysaccharide and peptidoglycan from bacteria in shrimp challenged using WSSV or bacteria, and it promoted the expression of a battery of antimicrobial peptides (AMPs) via the induction of Dorsal nuclear translocation against viral and bacterial infection. Moreover, LOXL expression was also positively regulated by Dorsal in the shrimp challenged by pathogens. These results indicate that, by acting as a pattern recognition receptor, LOXL plays vital roles in antiviral and antibacterial innate immunity by enhancing the expression of AMPs in shrimp.

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Garcia, Pierre S., Wandrille Duchemin, Jean-Pierre Flandrois, Simonetta Gribaldo, Christophe Grangeasse, and Céline Brochier-Armanet. "A Comprehensive Evolutionary Scenario of Cell Division and Associated Processes in the Firmicutes." Molecular Biology and Evolution 38, no. 6 (February 3, 2021): 2396–412. http://dx.doi.org/10.1093/molbev/msab034.

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Abstract The cell cycle is a fundamental process that has been extensively studied in bacteria. However, many of its components and their interactions with machineries involved in other cellular processes are poorly understood. Furthermore, most knowledge relies on the study of a few models, but the real diversity of the cell division apparatus and its evolution are largely unknown. Here, we present a massive in-silico analysis of cell division and associated processes in around 1,000 genomes of the Firmicutes, a major bacterial phylum encompassing models (i.e. Bacillus subtilis, Streptococcus pneumoniae, and Staphylococcus aureus), as well as many important pathogens. We analyzed over 160 proteins by using an original approach combining phylogenetic reconciliation, phylogenetic profiles, and gene cluster survey. Our results reveal the presence of substantial differences among clades and pinpoints a number of evolutionary hotspots. In particular, the emergence of Bacilli coincides with an expansion of the gene repertoires involved in cell wall synthesis and remodeling. We also highlight major genomic rearrangements at the emergence of Streptococcaceae. We establish a functional network in Firmicutes that allows identifying new functional links inside one same process such as between FtsW (peptidoglycan polymerase) and a previously undescribed Penicilin-Binding Protein or between different processes, such as replication and cell wall synthesis. Finally, we identify new candidates involved in sporulation and cell wall synthesis. Our results provide a previously undescribed view on the diversity of the bacterial cell cycle, testable hypotheses for further experimental studies, and a methodological framework for the analysis of any other biological system.

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Boersma, Michael J., Erkin Kuru, Jonathan T. Rittichier, Michael S. VanNieuwenhze, Yves V. Brun, and Malcolm E. Winkler. "Minimal Peptidoglycan (PG) Turnover in Wild-Type and PG Hydrolase and Cell Division Mutants of Streptococcus pneumoniae D39 Growing Planktonically and in Host-Relevant Biofilms." Journal of Bacteriology 197, no. 21 (August 24, 2015): 3472–85. http://dx.doi.org/10.1128/jb.00541-15.

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ABSTRACTWe determined whether there is turnover of the peptidoglycan (PG) cell wall of the ovococcus bacterial pathogenStreptococcus pneumoniae(pneumococcus). Pulse-chase experiments on serotype 2 strain D39 radiolabeled withN-acetylglucosamine revealed little turnover and release of PG breakdown products during growth compared to published reports of PG turnover inBacillus subtilis. PG dynamics were visualized directly by long-pulse–chase–new-labeling experiments using two colors offluorescentd-aminoacid (FDAA) probes to microscopically detect regions of new PG synthesis. Consistent with minimal PG turnover, hemispherical regions of stable “old” PG persisted in D39 and TIGR4 (serotype 4) cells grown in rich brain heart infusion broth, in D39 cells grown in chemically defined medium containing glucose or galactose as the carbon source, and in D39 cells grown as biofilms on a layer of fixed human epithelial cells. In contrast,B. subtilisexhibited rapid sidewall PG turnover in similar FDAA-labeling experiments. High-performance liquid chromatography (HPLC) analysis of biochemically released peptides fromS. pneumoniaePG validated that FDAAs incorporated at low levels into pentamer PG peptides and did not change the overall composition of PG peptides. PG dynamics were also visualized in mutants lacking PG hydrolases that mediate PG remodeling, cell separation, or autolysis and in cells lacking the MapZ and DivIVA division regulators. In all cases, hemispheres of stable old PG were maintained. In PG hydrolase mutants exhibiting aberrant division plane placement, FDAA labeling revealed patches of inert PG at turns and bulge points. We conclude that growingS. pneumoniaecells exhibit minimal PG turnover compared to the PG turnover in rod-shaped cells.IMPORTANCEPG cell walls are unique to eubacteria, and many bacterial species turn over and recycle their PG during growth, stress, colonization, and virulence. Consequently, PG breakdown products serve as signals for bacteria to induce antibiotic resistance and as activators of innate immune responses.S. pneumoniaeis a commensal bacterium that colonizes the human nasopharynx and opportunistically causes serious respiratory and invasive diseases. The results presented here demonstrate a distinct demarcation between regions of old PG and regions of new PG synthesis and minimal turnover of PG inS. pneumoniaecells growing in culture or in host-relevant biofilms. These findings suggest thatS. pneumoniaeminimizes the release of PG breakdown products by turnover, which may contribute to evasion of the innate immune system.

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Egan, Alexander J. F., Jeff Errington, and Waldemar Vollmer. "Regulation of peptidoglycan synthesis and remodelling." Nature Reviews Microbiology 18, no. 8 (May 18, 2020): 446–60. http://dx.doi.org/10.1038/s41579-020-0366-3.

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Hernández, Sara B., Felipe Cava, M. Graciela Pucciarelli, Francisco García-del Portillo, Miguel A. de Pedro, and Josep Casadesús. "Bile-induced peptidoglycan remodelling inSalmonella enterica." Environmental Microbiology 17, no. 4 (June 24, 2014): 1081–89. http://dx.doi.org/10.1111/1462-2920.12491.

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Lakey, Bryan D., Kevin S. Myers, François Alberge, Erin L. Mettert, Patricia J. Kiley, Daniel R. Noguera, and Timothy J. Donohue. "The essential Rhodobacter sphaeroides CenKR two-component system regulates cell division and envelope biosynthesis." PLOS Genetics 18, no. 6 (June 29, 2022): e1010270. http://dx.doi.org/10.1371/journal.pgen.1010270.

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Bacterial two-component systems (TCSs) often function through the detection of an extracytoplasmic stimulus and the transduction of a signal by a transmembrane sensory histidine kinase. This kinase then initiates a series of reversible phosphorylation modifications to regulate the activity of a cognate, cytoplasmic response regulator as a transcription factor. Several TCSs have been implicated in the regulation of cell cycle dynamics, cell envelope integrity, or cell wall development in Escherichia coli and other well-studied Gram-negative model organisms. However, many α-proteobacteria lack homologs to these regulators, so an understanding of how α-proteobacteria orchestrate extracytoplasmic events is lacking. In this work we identify an essential TCS, CenKR (Cell envelope Kinase and Regulator), in the α-proteobacterium Rhodobacter sphaeroides and show that modulation of its activity results in major morphological changes. Using genetic and biochemical approaches, we dissect the requirements for the phosphotransfer event between CenK and CenR, use this information to manipulate the activity of this TCS in vivo, and identify genes that are directly and indirectly controlled by CenKR in Rb. sphaeroides. Combining ChIP-seq and RNA-seq, we show that the CenKR TCS plays a direct role in maintenance of the cell envelope, regulates the expression of subunits of the Tol-Pal outer membrane division complex, and indirectly modulates the expression of peptidoglycan biosynthetic genes. CenKR represents the first TCS reported to directly control the expression of Tol-Pal machinery genes in Gram-negative bacteria, and we predict that homologs of this TCS serve a similar function in other closely related organisms. We propose that Rb. sphaeroides genes of unknown function that are directly regulated by CenKR play unknown roles in cell envelope biosynthesis, assembly, and/or remodeling in this and other α-proteobacteria.

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Culp, Elizabeth J., Nicholas Waglechner, Wenliang Wang, Aline A. Fiebig-Comyn, Yen-Pang Hsu, Kalinka Koteva, David Sychantha, et al. "Evolution-guided discovery of antibiotics that inhibit peptidoglycan remodelling." Nature 578, no. 7796 (February 2020): 582–87. http://dx.doi.org/10.1038/s41586-020-1990-9.

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Goley, Erin D., Luis R. Comolli, Katherine E. Fero, Kenneth H. Downing, and Lucy Shapiro. "DipM links peptidoglycan remodelling to outer membrane organization in Caulobacter." Molecular Microbiology 77, no. 1 (May 24, 2010): 56–73. http://dx.doi.org/10.1111/j.1365-2958.2010.07222.x.

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Thompson, L. S., P. L. Beech, G. Real, A. O. Henriques, and E. J. Harry. "Requirement for the Cell Division Protein DivIB in Polar Cell Division and Engulfment during Sporulation in Bacillus subtilis." Journal of Bacteriology 188, no. 21 (August 25, 2006): 7677–85. http://dx.doi.org/10.1128/jb.01072-06.

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ABSTRACT During spore formation in Bacillus subtilis, cell division occurs at the cell pole and is believed to require essentially the same division machinery as vegetative division. Intriguingly, although the cell division protein DivIB is not required for vegetative division at low temperatures, it is essential for efficient sporulation under these conditions. We show here that at low temperatures in the absence of DivIB, formation of the polar septum during sporulation is delayed and less efficient. Furthermore, the polar septa that are complete are abnormally thick, containing more peptidoglycan than a normal polar septum. These results show that DivIB is specifically required for the efficient and correct formation of a polar septum. This suggests that DivIB is required for the modification of sporulation septal peptidoglycan, raising the possibility that DivIB either regulates hydrolysis of polar septal peptidoglycan or is a hydrolase itself. We also show that, despite the significant number of completed polar septa that form in this mutant, it is unable to undergo engulfment. Instead, hydrolysis of the peptidoglycan within the polar septum, which occurs during the early stages of engulfment, is incomplete, producing a similar phenotype to that of mutants defective in the production of sporulation-specific septal peptidoglycan hydrolases. We propose a role for DivIB in sporulation-specific peptidoglycan remodelling or its regulation during polar septation and engulfment.

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Maitra, Arundhati, Tulika Munshi, Jess Healy, Liam T. Martin, Waldemar Vollmer, Nicholas H. Keep, and Sanjib Bhakta. "Cell wall peptidoglycan in Mycobacterium tuberculosis: An Achilles’ heel for the TB-causing pathogen." FEMS Microbiology Reviews 43, no. 5 (June 10, 2019): 548–75. http://dx.doi.org/10.1093/femsre/fuz016.

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ABSTRACTTuberculosis (TB), caused by the intracellular pathogen Mycobacterium tuberculosis, remains one of the leading causes of mortality across the world. There is an urgent requirement to build a robust arsenal of effective antimicrobials, targeting novel molecular mechanisms to overcome the challenges posed by the increase of antibiotic resistance in TB. Mycobacterium tuberculosis has a unique cell envelope structure and composition, containing a peptidoglycan layer that is essential for maintaining cellular integrity and for virulence. The enzymes involved in the biosynthesis, degradation, remodelling and recycling of peptidoglycan have resurfaced as attractive targets for anti-infective drug discovery. Here, we review the importance of peptidoglycan, including the structure, function and regulation of key enzymes involved in its metabolism. We also discuss known inhibitors of ATP-dependent Mur ligases, and discuss the potential for the development of pan-enzyme inhibitors targeting multiple Mur ligases.

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Machowski, Edith, Sibusiso Senzani, Christopher Ealand, and Bavesh Kana. "Comparative genomics for mycobacterial peptidoglycan remodelling enzymes reveals extensive genetic multiplicity." BMC Microbiology 14, no. 1 (2014): 75. http://dx.doi.org/10.1186/1471-2180-14-75.

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Chan, Anson, Yanjie Liu, Kris Blair, Emilisa Frirdich, Erin Gaynor, Nina Salama, Martin Tanner, and Michael Murphy. "Helicobacter pylori Csd4 is a peptidoglycan metallocarboxypeptidase." Acta Crystallographica Section A Foundations and Advances 70, a1 (August 5, 2014): C442. http://dx.doi.org/10.1107/s2053273314095576.

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The bacterial cell wall is a polymeric structure that determines the overall shape of the cell and undergoes constant remodelling during cell growth, requiring enzymes that cleave the existing peptidoglycan structure. Csd4 is an enzyme important for cell shape as deleting it in Helicobacter pylori causes the helical-shaped cells to become rod-like. Csd4 is a zinc carboxypeptidase that can cleave the tripeptide moiety found in peptidoglycan (i.e. L-Ala-γ-D-Glu-m-DAP) to release meso-diaminopimelic acid (mDAP). Structures of Csd4 were solved by X-ray crystallography up to 1.75 Å resolution in space group P212121 with zinc and substrate/product bound and contain the same unit cell dimensions. Csd4 is a monomeric enzyme with three domains: an N-terminal M14-family carboxypeptidase domain followed by two smaller domains likely important in protein-protein or protein-peptidoglycan interactions. Key interactions are observed between the protein and substrate in the active site, supporting specific substrate recognition by Csd4. A water or hydroxide molecule, which is required for catalytic activity, is also observed bound to the zinc and is poised to interact with the substrate molecule upon activation.

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Pandey, Satya Deo, Diamond Jain, Neeraj Kumar, Anwesha Adhikary, Ganesh Kumar N., and Anindya S. Ghosh. "MSMEG_2432 of Mycobacterium smegmatis mc2155 is a dual function enzyme that exhibits DD-carboxypeptidase and β-lactamase activities." Microbiology 166, no. 6 (June 1, 2020): 546–53. http://dx.doi.org/10.1099/mic.0.000902.

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Mycobacterial peptidoglycan (PG) is an unsolved puzzle due to its complex structure and involvement of multiple enzymes in the process of its remodelling. dd-Carboxypeptidases are low molecular mass penicillin-binding proteins (LMM-PBPs) that catalyzes the cleavage of terminal d-Ala of muramyl pentapeptide branches and thereby helps in the PG remodelling process. Here, we have assigned the function of a putative LMM-PBP, MSMEG_2432 of Mycobacterium smegmatis , by showing that it exhibits both dd-CPase and β-lactamase activities. Like conventional dd-CPase (PBP5 from E. coli), upon ectopic complementation in a deformed seven PBP deletion mutant of E. coli, MSMEG_2432 has manifested its ability to restore ~75 % of the cell population to their normal rod shape. Further, in vitro dd-CPase assay has confirmed its ability to release terminal d-Ala from the synthetic tripeptide and the peptidoglycan mimetic pentapeptide substrates ending with d-Ala-d-Ala. Also, elevated resistance against penicillins and cephalosporins upon ectopic expression of MSMEG_2432 suggests the presence of β-lactamase activity, which is further confirmed in vitro through nitrocefin hydrolysis assay. Moreover, it is found apparent that D169A substitution in MSMEG_2432 influences both of its in vivo and in vitro dd-CPase and β-lactamase activities. Thus, we infer that MSMEG_2432 is a dual function enzyme that possesses both dd-CPase and β-lactamase activities.

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Journal articles on the topic 'Peptidoglycan remodeling'

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