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Journal articles on the topic 'Transpeptidases'

Author: Grafiati

Published: 4 June 2021

Last updated: 25 May 2024

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1

Jacobs, Lian M. C., Patrick Consol, and Yu Chen. "Drug Discovery in the Field of β-Lactams: An Academic Perspective." Antibiotics 13, no. 1 (January 8, 2024): 59. http://dx.doi.org/10.3390/antibiotics13010059.

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β-Lactams are the most widely prescribed class of antibiotics that inhibit penicillin-binding proteins (PBPs), particularly transpeptidases that function in peptidoglycan synthesis. A major mechanism of antibiotic resistance is the production of β-lactamase enzymes, which are capable of hydrolyzing β-lactam antibiotics. There have been many efforts to counter increasing bacterial resistance against β-lactams. These studies have mainly focused on three areas: discovering novel inhibitors against β-lactamases, developing new β-lactams less susceptible to existing resistance mechanisms, and identifying non-β-lactam inhibitors against cell wall transpeptidases. Drug discovery in the β-lactam field has afforded a range of research opportunities for academia. In this review, we summarize the recent new findings on both β-lactamases and cell wall transpeptidases because these two groups of enzymes are evolutionarily and functionally connected. Many efforts to develop new β-lactams have aimed to inhibit both transpeptidases and β-lactamases, while several promising novel β-lactamase inhibitors have shown the potential to be further developed into transpeptidase inhibitors. In addition, the drug discovery progress against each group of enzymes is presented in three aspects: understanding the targets, screening methodology, and new inhibitor chemotypes. This is to offer insights into not only the advancement in this field but also the challenges, opportunities, and resources for future research. In particular, cyclic boronate compounds are now capable of inhibiting all classes of β-lactamases, while the diazabicyclooctane (DBO) series of small molecules has led to not only new β-lactamase inhibitors but potentially a new class of antibiotics by directly targeting PBPs. With the cautiously optimistic successes of a number of new β-lactamase inhibitor chemotypes and many questions remaining to be answered about the structure and function of cell wall transpeptidases, non-β-lactam transpeptidase inhibitors may usher in the next exciting phase of drug discovery in this field.

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2

Pishesha, Novalia, Jessica R. Ingram, and Hidde L. Ploegh. "Sortase A: A Model for Transpeptidation and Its Biological Applications." Annual Review of Cell and Developmental Biology 34, no. 1 (October 6, 2018): 163–88. http://dx.doi.org/10.1146/annurev-cellbio-100617-062527.

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Molecular biologists and chemists alike have long sought to modify proteins with substituents that cannot be installed by standard or even advanced genetic approaches. We here describe the use of transpeptidases to achieve these goals. Living systems encode a variety of transpeptidases and peptide ligases that allow for the enzyme-catalyzed formation of peptide bonds, and protein engineers have used directed evolution to enhance these enzymes for biological applications. We focus primarily on the transpeptidase sortase A, which has become popular over the past few years for its ability to perform a remarkably wide variety of protein modifications, both in vitro and in living cells.

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3

Mercer, Keri L. N., and David S. Weiss. "The Escherichia coli Cell Division Protein FtsW Is Required To Recruit Its Cognate Transpeptidase, FtsI (PBP3), to the Division Site." Journal of Bacteriology 184, no. 4 (February 15, 2002): 904–12. http://dx.doi.org/10.1128/jb.184.4.904-912.2002.

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ABSTRACT The bacterial cell division protein FtsW has been suggested to perform two functions: stabilize the FtsZ cytokinetic ring, and facilitate septal peptidoglycan synthesis by the transpeptidase FtsI (penicillin-binding protein 3). We show here that depleting Escherichia coli cells of FtsW had little effect on the abundance of FtsZ rings but abrogated recruitment of FtsI to potential division sites. Analysis of FtsW localization confirmed and extended these results; septal localization of FtsW required FtsZ, FtsA, FtsQ, and FtsL but not FtsI. Thus, FtsW is a late recruit to the division site and is essential for subsequent recruitment of its cognate transpeptidase FtsI but not for stabilization of FtsZ rings. We suggest that a primary function of FtsW homologues—which are found in almost all bacteria and appear to work in conjunction with dedicated transpeptidases involved in division, elongation, or sporulation—is to recruit their cognate transpeptidases to the correct subcellular location.

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4

Hugonnet, Jean-Emmanuel, Nabila Haddache, Carole Veckerlé, Lionel Dubost, Arul Marie, Noriyasu Shikura, Jean-Luc Mainardi, Louis B. Rice, and Michel Arthur. "Peptidoglycan Cross-Linking in Glycopeptide-Resistant Actinomycetales." Antimicrobial Agents and Chemotherapy 58, no. 3 (January 6, 2014): 1749–56. http://dx.doi.org/10.1128/aac.02329-13.

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ABSTRACTSynthesis of peptidoglycan precursors ending ind-lactate (d-Lac) is thought to be responsible for glycopeptide resistance in members of the orderActinomycetalesthat produce these drugs and in related soil bacteria. More recently, the peptidoglycan of several members of the orderActinomycetaleswas shown to be cross-linked byl,d-transpeptidases that use tetrapeptide acyl donors devoid of the target of glycopeptides. To evaluate the contribution of these resistance mechanisms, we have determined the peptidoglycan structure ofStreptomyces coelicolorA(3)2, which harbors avanHAXgene cluster for the production of precursors ending ind-Lac, andNonomuraeasp. strain ATCC 39727, which is devoid ofvanHAXand produces the glycopeptide A40296. Vancomycin retained residual activity againstS. coelicolorA(3)2 despite efficient incorporation ofd-Lac into cytoplasmic precursors. This was due to ad,d-transpeptidase-catalyzed reaction that generated a stem pentapeptide recognized by glycopeptides by the exchange ofd-Lac ford-Ala and Gly. The contribution ofl,d-transpeptidases to resistance was limited by the supply of tetrapeptide acyl donors, which are essential for the formation of peptidoglycan cross-links by these enzymes. In the absence of a cytoplasmic metallo-d,d-carboxypeptidase, the tetrapeptide substrate was generated by hydrolysis of the C-terminald-Lac residue of the stem pentadepsipeptide in the periplasm in competition with the exchange reaction catalyzed byd,d-transpeptidases. InNonomuraeasp. strain ATCC 39727, the contribution ofl,d-transpeptidases to glycopeptide resistance was limited by the incomplete conversion of pentapeptides into tetrapeptides despite the production of a cytoplasmic metallo-d,d-carboxypeptidase. Since the level of drug production exceeds the level of resistance, we propose thatl,d-transpeptidases merely act as a tolerance mechanism in this bacterium.

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5

Magnet, Sophie, Lionel Dubost, Arul Marie, Michel Arthur, and Laurent Gutmann. "Identification of the l,d-Transpeptidases for Peptidoglycan Cross-Linking in Escherichia coli." Journal of Bacteriology 190, no. 13 (May 2, 2008): 4782–85. http://dx.doi.org/10.1128/jb.00025-08.

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ABSTRACT Three active-site cysteine l,d-transpeptidases can individually anchor the Braun lipoprotein to the Escherichia coli peptidoglycan. We show here that two additional enzymes of the same family form peptide bonds between the third residues of peptidoglycan stems, generating meso-DAP3→meso-DAP3 unusual cross-links. This activity partially replaces the d,d-transpeptidase activity of penicillin-binding proteins.

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6

Bahadur, Raj, Pavan Kumar Chodisetti, and Manjula Reddy. "Cleavage of Braun’s lipoprotein Lpp from the bacterial peptidoglycan by a paralog of l,d-transpeptidases, LdtF." Proceedings of the National Academy of Sciences 118, no. 19 (May 3, 2021): e2101989118. http://dx.doi.org/10.1073/pnas.2101989118.

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The gram‐negative bacterial cell envelope is made up of an outer membrane (OM), an inner membrane (IM) that surrounds the cytoplasm, and a periplasmic space between the two membranes containing peptidoglycan (PG or murein). PG is an elastic polymer that forms a mesh-like sacculus around the IM, protecting cells from turgor and environmental stress conditions. In several bacteria, including Escherichia coli, the OM is tethered to PG by an abundant OM lipoprotein, Lpp (or Braun’s lipoprotein), that functions to maintain the structural and functional integrity of the cell envelope. Since its discovery, Lpp has been studied extensively, and although l,d-transpeptidases, the enzymes that catalyze the formation of PG−Lpp linkages, have been earlier identified, it is not known how these linkages are modulated. Here, using genetic and biochemical approaches, we show that LdtF (formerly yafK), a newly identified paralog of l,d-transpeptidases in E. coli, is a murein hydrolytic enzyme that catalyzes cleavage of Lpp from the PG sacculus. LdtF also exhibits glycine-specific carboxypeptidase activity on muropeptides containing a terminal glycine residue. LdtF was earlier presumed to be an l,d-transpeptidase; however, our results show that it is indeed an l,d-endopeptidase that hydrolyzes the products generated by the l,d-transpeptidases. To summarize, this study describes the discovery of a murein endopeptidase with a hitherto unknown catalytic specificity that removes the PG−Lpp cross-links, suggesting a role for LdtF in the regulation of PG–OM linkages to maintain the structural integrity of the bacterial cell envelope.

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7

Dubée, Vincent, Sébastien Triboulet, Jean-Luc Mainardi, Mélanie Ethève-Quelquejeu, Laurent Gutmann, Arul Marie, Lionel Dubost, Jean-Emmanuel Hugonnet, and Michel Arthur. "Inactivation of Mycobacterium tuberculosis l,d-Transpeptidase LdtMt1by Carbapenems and Cephalosporins." Antimicrobial Agents and Chemotherapy 56, no. 8 (May 21, 2012): 4189–95. http://dx.doi.org/10.1128/aac.00665-12.

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ABSTRACTThe structure ofMycobacterium tuberculosispeptidoglycan is atypical since it contains a majority of 3→3 cross-links synthesized byl,d-transpeptidases that replace 4→3 cross-links formed by thed,d-transpeptidase activity of classical penicillin-binding proteins. Carbapenems inactivate thesel,d-transpeptidases, and meropenem combined with clavulanic acid is bactericidal against extensively drug-resistantM. tuberculosis. Here, we used mass spectrometry and stopped-flow fluorimetry to investigate the kinetics and mechanisms of inactivation of the prototypicM. tuberculosisl,d-transpeptidase LdtMt1by carbapenems (meropenem, doripenem, imipenem, and ertapenem) and cephalosporins (cefotaxime, cephalothin, and ceftriaxone). Inactivation proceeded through noncovalent drug binding and acylation of the catalytic Cys of LdtMt1, which was eventually followed by hydrolysis of the resulting acylenzyme. Meropenem rapidly inhibited LdtMt1, with a binding rate constant of 0.08 μM−1min−1. The enzyme was unable to recover from this initial binding step since the dissociation rate constant of the noncovalent complex was low (<0.1 min−1) in comparison to the acylation rate constant (3.1 min−1). The covalent adduct resulting from enzyme acylation was stable, with a hydrolysis rate constant of 1.0 × 10−3min−1. Variations in the carbapenem side chains affected both the binding and acylation steps, ertapenem being the most efficient LdtMt1inactivator. Cephalosporins also formed covalent adducts with LdtMt1, although the acylation reaction was 7- to 1,000-fold slower and led to elimination of one of the drug side chains. Comparison of kinetic constants for drug binding, acylation, and acylenzyme hydrolysis indicates that carbapenems and cephems can both be tailored to optimize peptidoglycan synthesis inhibition inM. tuberculosis.

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8

Tolufashe, Gideon F., Victor T. Sabe, Colins U. Ibeji, Thandokuhle Ntombela, Thavendran Govender, Glenn E. M. Maguire, Hendrik G. Kruger, Gyanu Lamichhane, and Bahareh Honarparvar. "Structure and Function of L,D- and D,D-Transpeptidase Family Enzymes from Mycobacterium tuberculosis." Current Medicinal Chemistry 27, no. 19 (June 4, 2020): 3250–67. http://dx.doi.org/10.2174/0929867326666181203150231.

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Peptidoglycan, the exoskeleton of bacterial cell and an essential barrier that protects the cell, is synthesized by a pathway where the final steps are catalysed by transpeptidases. Knowledge of the structure and function of these vital enzymes that generate this macromolecule in M. tuberculosis could facilitate the development of potent lead compounds against tuberculosis. This review summarizes the experimental and computational studies to date on these aspects of transpeptidases in M. tuberculosis that have been identified and validated. The reported structures of L,D- and D,D-transpeptidases, as well as their functionalities, are reviewed and the proposed enzymatic mechanisms for L,D-transpeptidases are summarized. In addition, we provide bioactivities of known tuberculosis drugs against these enzymes based on both experimental and computational approaches. Advancing knowledge about these prominent targets supports the development of new drugs with novel inhibition mechanisms overcoming the current need for new drugs against tuberculosis.

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9

Nguyen, David, Christopher Bethel, Magdalena A. Taracilla, Qing Li, Khalid M. Dousa, Sebastian G. Kurz, Liem Nguyen, Barry N. Kreiswirth, Wilem Boom, and Robert A. Bonomo. "1390. Durlobactam, a Diazabicyclooctane (DBO) β-lactamase Inhibitor (BLI), Inhibits BlaC and Peptidoglycan (PG) Transpeptidases of Mycobacterium tuberculosis (Mtb): A Novel Approach to Therapeutics for Tuberculosis (TB)?" Open Forum Infectious Diseases 8, Supplement_1 (November 1, 2021): S780. http://dx.doi.org/10.1093/ofid/ofab466.1582.

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Abstract Background Novel therapies for multidrug-resistant TB are needed and new BLIs could answer this call. Mtb encodes for BlaC, a class A β-lactamase. BlaC is inhibited by clavulanate (CLA) while the DBO avibactam (AVI) is an inefficient inhibitor (low k2/K value). Carbapenems are hydrolyzed slowly by BlaC (low kcat/Km value) making them “dual action” compounds that inhibit both BlaC and PG transpeptidases, the intended β-lactam targets. DBOs inhibit PG transpeptidases in other bacteria. To explore the therapeutic potential of new DBOs against Mtb, we compared the inhibitor activity of AVI, relebactam (REL), and durlobactam (DUR, formerly ETX2514) against BlaC and Mtb PG transpeptidases using a biochemical approach. We also investigated the ability of DUR to lower minimum inhibitory concentrations (MICs) of β-lactams against Mtb H37Rv. Methods Mass spectrometry was performed to capture acyl-enzyme complexes (AECs) of purified BlaC and PG transpeptidases (PonA1, LdtMt1, LdtMt2, LdtMt3, and LdtMt5) with β-lactams and BLIs. Steady-state enzyme kinetics were determined using nitrocefin as a substrate. MICs with amoxicillin (AMX), meropenem (MER), CLA, and DUR alone and in combination against Mtb H37Rv were assessed using a microdilution method. Results DUR alone had a MIC of 2 µg/mL with Mtb H37Rv (Table 1). BlaC formed AECs with all carbapenems and BLIs. BlaC had lower Ki app and higher k2/K with DUR than those with AVI and REL and comparable to those with CLA; however, with a period of pre-incubation, AVI fully inhibits BlaC (Table 2). The carbapenems and DUR formed the most AECs with PG transpeptidases of the β-lactams and BLIs respectively; PG transpeptidases had lower Ki app values with DUR than those with AVI (Table 3). Table 1. Minimum Inhibitory Concetrations for Mycobacterium tuberculosis H37Rv Conclusion DUR alone has some antimicrobial activity against Mtb H37Rv. The likely mechanism that underlies this activity is inhibition of BlaC and several PG transpeptidases. Inhibition of enzyme targets with DUR was more potent and efficient than AVI and REL. DUR in combination with β-lactams lowered MICs but the DUR concentration used was higher than its MIC. Our findings support the exploration of novel BLIs against BlaC and PG transpeptidases with the ultimate goal of repurposing these drugs for the treatment of TB. Disclosures Robert A. Bonomo, MD, entasis (Research Grant or Support)Merck (Grant/Research Support)NIH (Grant/Research Support)VA Merit Award (Grant/Research Support)VenatoRx (Grant/Research Support)

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Biliuk, A., L. Garmanchuk, O. Skachkova, H. Repich, and S. Orysyk. "Antineoplastic, anti-metastatic and metabolic effects of newly synthesized platinum complexes." Bulletin of Taras Shevchenko National University of Kyiv. Series: Problems of Physiological Functions Regulation 23, no. 2 (2017): 69–75. http://dx.doi.org/10.17721/2616_6410.2017.23.69-75.

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The aim of this work was to study the antitumor, anti-metastatic and metabolic effects of the newly synthesized n, π-chelate complexes Pt2+ with N-allythioureas (complex II and IU complex). The studies used high-metastable strain of transfected Lewis lung carcinoma and HepG2-transformed hepatocyte cells with high activity gamma-glutamate transpeptidases and mouse leukemia cells of L1210 with pronounced aneuploid karyotype and short duplication of population. In the comparative analysis with the classical chemotherapy cisplatin, the II and IV complexes revealed antitumor and anti-metastatic effects and normalization of biochemical disorders, which are confirmed by a decrease in the activity of lactate dehydrogenase and gamma-glutamine transpeptidase, indicating the inhibition of the formation of drug resistance.

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de Munnik, Mariska, Christopher T. Lohans, Pauline A. Lang, Gareth W. Langley, Tika R. Malla, Anthony Tumber, Christopher J. Schofield, and Jürgen Brem. "Targeting the Mycobacterium tuberculosis transpeptidase LdtMt2 with cysteine-reactive inhibitors including ebselen." Chemical Communications 55, no. 69 (2019): 10214–17. http://dx.doi.org/10.1039/c9cc04145a.

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De, Soumya, and Lawrence P. McIntosh. "Putting a Stop to l,d-Transpeptidases." Structure 20, no. 5 (May 2012): 753–54. http://dx.doi.org/10.1016/j.str.2012.04.005.

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Sanders, Akeisha N., Lori F. Wright, and Martin S. Pavelka. "Genetic characterization of mycobacterial l,d-transpeptidases." Microbiology 160, no. 8 (August 1, 2014): 1795–806. http://dx.doi.org/10.1099/mic.0.078980-0.

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l,d-Transpeptidases (Ldts) catalyse the formation of 3–3 cross-links in peptidoglycans (PGs); however, the role of these enzymes in cell envelope physiology is not well understood. Mycobacterial PG contains a higher percentage of 3–3 cross-links (~30–80 %) than the PG in most other bacteria, suggesting that they are particularly important to mycobacterial cell wall biology. The genomes of Mycobacterium tuberculosis and Mycobacterium smegmatis encode multiple Ldt genes, but it is not clear if they are redundant. We compared the sequences of the Ldt proteins from 18 mycobacterial genomes and found that they can be grouped into six classes. We then constructed M. smegmatis strains lacking single or multiple Ldt genes to determine the physiological consequence of the loss of these enzymes. We report that of the single mutants, only one, ΔldtC (MSMEG_0929, class 5), displayed an increased susceptibility to imipenem – a carbapenem antibiotic that inhibits the Ldt enzymes. The invariant cysteine in the active site of LdtC was required for function, consistent with its role as an Ldt. A triple mutant missing ldtC and both of the class 2 genes displayed hypersusceptibility to antibiotics, lysozyme and d-methionine, and had an altered cellular morphology. These data demonstrated that the distinct classes of mycobacterial Ldts may reflect different, non-redundant functions and that the class 5 Ldt was peculiar in that its loss, alone and with the class 2 proteins, had the most profound effect on phenotype.

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King, Dustin, and Natalie Strynadka. "Analysis of bacterial cell-wall synthesis to combat antibiotic resistance." Acta Crystallographica Section A Foundations and Advances 70, a1 (August 5, 2014): C701. http://dx.doi.org/10.1107/s2053273314092985.

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The peptidoglycan biosynthetic pathway is one of the most important processes in the bacterial cell to be exploited as a target for the design of antimicrobial drugs to combat infection and pathogenesis. This pathway, unique to bacteria, utilizes over twenty enzymes, likely in concert, with reactions that proceed from the cytoplasm, across the membrane and into the periplasmic space culminating in the production of the mesh-like structure composed of polymerized glycan and cross-linked peptide components that form the major structural component of the essential bacterial protective barrier known as the cell wall. Work in our group has aimed at understanding the structural and kinetic properties of several of these enzymes including the glycosyltransferase/transpeptidase activity of a family of enzymes known historically as the penicillin binding proteins (PBPs). As the name implies, these enzymes are also the target of beta-lactam antibiotics, and molecular modifications to transpeptidase variants have been shown to be linked to increased antibiotic resistance in superbugs such as Methicillin Resistant Staphlococcal aureus (MRSA). In parallel, highly disseminated plasmid-encoded beta-lactamase enzymes, with structural and mechanistic ties to the transpeptidases, have also arisen in many of the clinically important bacterial pathogens, leading to further widespread beta-lactam antibiotic resistance. The molecular details of these critical enzymatic reactions in bacterial viability and drug resistance will be presented.

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Zandi, Trevor A., and Craig A. Townsend. "Competing off-loading mechanisms of meropenem from an l,d-transpeptidase reduce antibiotic effectiveness." Proceedings of the National Academy of Sciences 118, no. 27 (June 29, 2021): e2008610118. http://dx.doi.org/10.1073/pnas.2008610118.

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The carbapenem family of β-lactam antibiotics displays a remarkably broad spectrum of bactericidal activity, exemplified by meropenem’s phase II clinical trial success in patients with pulmonary tuberculosis, a devastating disease for which β-lactam drugs historically have been notoriously ineffective. The discovery and validation of l,d-transpeptidases (Ldts) as critical drug targets of bacterial cell-wall biosynthesis, which are only potently inhibited by the carbapenem and penem structural classes, gave an enzymological basis for the effectiveness of the first antitubercular β-lactams. Decades of study have delineated mechanisms of β-lactam inhibition of their canonical targets, the penicillin-binding proteins; however, open questions remain regarding the mechanisms of Ldt inhibition that underlie programs in drug design, particularly the optimization of kinetic behavior and potency. We have investigated critical features of mycobacterial Ldt inhibition and demonstrate here that the covalent inhibitor meropenem undergoes both reversible reaction and nonhydrolytic off-loading reactions from the cysteine transpeptidase LdtMt2 through a high-energy thioester adduct. Next-generation carbapenem optimization strategies should minimize adduct loss from unproductive mechanisms of Ldt adducts that reduce effective drug concentration.

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Kumar, Pankaj, Amit Kaushik, Evan P. Lloyd, Shao-Gang Li, Rohini Mattoo, Nicole C. Ammerman, Drew T. Bell, et al. "Non-classical transpeptidases yield insight into new antibacterials." Nature Chemical Biology 13, no. 1 (November 7, 2016): 54–61. http://dx.doi.org/10.1038/nchembio.2237.

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Tate, Suresh S., Vijay Khadse, and Daniel Wellner. "Renal γ-glutamyl transpeptidases: Structural and immunological studies." Archives of Biochemistry and Biophysics 262, no. 2 (May 1988): 397–408. http://dx.doi.org/10.1016/0003-9861(88)90390-6.

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Nguyen, Lam T., James C. Gumbart, Morgan Beeby, and Grant J. Jensen. "Coarse-grained simulations of bacterial cell wall growth reveal that local coordination alone can be sufficient to maintain rod shape." Proceedings of the National Academy of Sciences 112, no. 28 (June 30, 2015): E3689—E3698. http://dx.doi.org/10.1073/pnas.1504281112.

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Bacteria are surrounded by a peptidoglycan (PG) cell wall that must be remodeled to allow cell growth. While many structural details and properties of PG and the individual enzymes involved are known, how the process is coordinated to maintain cell integrity and rod shape is not understood. We have developed a coarse-grained method to simulate how individual transglycosylases, transpeptidases, and endopeptidases could introduce new material into an existing unilayer PG network. We find that a simple model with no enzyme coordination fails to maintain cell wall integrity and rod shape. We then iteratively analyze failure modes and explore different mechanistic hypotheses about how each problem might be overcome by the macromolecules involved. In contrast to a current theory, which posits that long MreB filaments are needed to coordinate PG insertion sites, we find that local coordination of enzyme activities in individual complexes can be sufficient to maintain cell integrity and rod shape. We also present possible molecular explanations for the existence of monofunctional transpeptidases and glycosidases (glycoside hydrolases), trimeric peptide crosslinks, cell twisting during growth, and synthesis of new strands in pairs.

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Clancy, Kathleen W., Jeffrey A. Melvin, and Dewey G. McCafferty. "Sortase transpeptidases: Insights into mechanism, substrate specificity, and inhibition." Biopolymers 94, no. 4 (June 30, 2010): 385–96. http://dx.doi.org/10.1002/bip.21472.

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Łęski, Tomasz A., and Alexander Tomasz. "Role of Penicillin-Binding Protein 2 (PBP2) in the Antibiotic Susceptibility and Cell Wall Cross-Linking of Staphylococcus aureus: Evidence for the Cooperative Functioning of PBP2, PBP4, and PBP2A." Journal of Bacteriology 187, no. 5 (March 1, 2005): 1815–24. http://dx.doi.org/10.1128/jb.187.5.1815-1824.2005.

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ABSTRACT Ceftizoxime, a beta-lactam antibiotic with high selective affinity for penicillin-binding protein 2 (PBP2) of Staphylococcus aureus, was used to select a spontaneous resistant mutant of S. aureus strain 27s. The stable resistant mutant ZOX3 had an increased ceftizoxime MIC and a decreased affinity of its PBP2 for ceftizoxime and produced peptidoglycan in which the proportion of highly cross-linked muropeptides was reduced. The pbpB gene of ZOX3 carried a single C-to-T nucleotide substitution at nucleotide 1373, causing replacement of a proline with a leucine at amino acid residue 458 of the transpeptidase domain of the protein, close to the SFN conserved motif. Experimental proof that this point mutation was responsible for the drug-resistant phenotype, and also for the decreased PBP2 affinity and reduced cell wall cross-linking, was provided by allelic replacement experiments and site-directed mutagenesis. Disruption of pbpD, the structural gene of PBP4, in either the parental strain or the mutant caused a large decrease in the highly cross-linked muropeptide components of the cell wall and in the mutant caused a massive accumulation of muropeptide monomers as well. Disruption of pbpD also caused increased sensitivity to ceftizoxime in both the parental cells and the ZOX3 mutant, while introduction of the plasmid-borne mecA gene, the genetic determinant of the beta-lactam resistance protein PBP2A, had the opposite effects. The findings provide evidence for the cooperative functioning of two native S. aureus transpeptidases (PBP2 and PBP4) and an acquired transpeptidase (PBP2A) in staphylococcal cell wall biosynthesis and susceptibility to antimicrobial agents.

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Cordillot, Mathilde, Vincent Dubée, Sébastien Triboulet, Lionel Dubost, Arul Marie, Jean-Emmanuel Hugonnet, Michel Arthur, and Jean-Luc Mainardi. "In VitroCross-Linking of Mycobacterium tuberculosis Peptidoglycan by l,d-Transpeptidases and Inactivation of These Enzymes by Carbapenems." Antimicrobial Agents and Chemotherapy 57, no. 12 (September 16, 2013): 5940–45. http://dx.doi.org/10.1128/aac.01663-13.

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ABSTRACTTheMycobacterium tuberculosispeptidoglycan is cross-linked mainly byl,d-transpeptidases (LDTs), which are efficiently inactivated by a single β-lactam class, the carbapenems. Development of carbapenems for tuberculosis treatment has recently raised considerable interest since these drugs, in association with the β-lactamase inhibitor clavulanic acid, are uniformly active against extensively drug-resistantM. tuberculosisand kill both exponentially growing and dormant forms of the bacilli. We have purified the fivel,d-transpeptidase paralogues ofM. tuberculosis(Mt1 to -5) and compared their activities with those of peptidoglycan fragments and carbapenems. The five LDTs were functionalin vitrosince they were active in assays of peptidoglycan cross-linking (Mt5), β-lactam acylation (Mt3), or both (Mt1, Mt2, and Mt4). Mt3 was the only LDT that was inactive in the cross-linking assay, suggesting that this enzyme might be involved in other cellular functions such as the anchoring of proteins to peptidoglycan, as shown inEscherichia coli. Inactivation of LDTs by carbapenems is a two-step reaction comprising reversible formation of a tetrahedral intermediate, the oxyanion, followed by irreversible rupture of the β-lactam ring that leads to formation of a stable acyl enzyme. Determination of the rate constants for these two steps revealed important differences (up to 460-fold) between carbapenems, which affected the velocity of oxyanion and acyl enzyme formation. Imipenem inactivated LDTs more rapidly than ertapenem, and both drugs were more efficient than meropenem and doripenem, indicating that modification of the carbapenem side chain could be used to optimize their antimycobacterial activity.

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Sanders, Akeisha N., and Martin S. Pavelka. "Phenotypic analysis of Eschericia coli mutants lacking l,d-transpeptidases." Microbiology 159, Pt_9 (September 1, 2013): 1842–52. http://dx.doi.org/10.1099/mic.0.069211-0.

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Sauvage, Eric, and Mohammed Terrak. "Glycosyltransferases and Transpeptidases/Penicillin-Binding Proteins: Valuable Targets for New Antibacterials." Antibiotics 5, no. 1 (February 17, 2016): 12. http://dx.doi.org/10.3390/antibiotics5010012.

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Smith, T. K., Y. Ikeda, J. Fujii, N. Taniguchi, and A. Meister. "Different sites of acivicin binding and inactivation of gamma-glutamyl transpeptidases." Proceedings of the National Academy of Sciences 92, no. 6 (March 14, 1995): 2360–64. http://dx.doi.org/10.1073/pnas.92.6.2360.

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Kastrinsky, David B., and Clifton E. Barry. "Synthesis of labeled meropenem for the analysis of M. tuberculosis transpeptidases." Tetrahedron Letters 51, no. 1 (January 2010): 197–200. http://dx.doi.org/10.1016/j.tetlet.2009.10.124.

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Mascaretti, O. A., C. E. Boschetti, G. O. Danelon, E. G. Mata, and O. A. Roveri. "β-Lactam Compounds. Inhibitors of Transpeptidases, β-Lactamases and Elastases: A Review." Current Medicinal Chemistry 1, no. 6 (April 1995): 441–70. http://dx.doi.org/10.2174/092986730106220216112824.

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Abstract: There are three classes of serine proteases that specifically recognise and cleave the cyclic amide bond of the four membered P lactam ring. One class is the bacterial D-alanyi-D-alanine transpeptidases/ carboxypeptidases or D,D-peptidase enzymes, which are the inhibitory targets for p-lactam antibiotics. The second group are the bacterial P lactamases, which catalyse the hydrolysis of the P-lactam antibiotics, yielding biologically inactive products.The third group are elastases, particularly the mammalian human leukocyte elastase which is a serine protease that uses the catalytic triad of Ser-195, His-57 and Asp-102, to catalyse the cleavage of the amide bonds of peptides and various proteins, including elastin, the connective tissue of the lung. The mechanism by which the three classes of enzymes cleave amide bond involves the nucleophilic addition of the hydroxyl group of an active site serine to the carbonyl carbon of the cleavable P-lactam bond and formation of a tetrahedral intermediate that collapses to an acyl enzyme intermediate. P-Lactamases differ from D,D-peptidases in that they catalyse the dea cylation step very efficiently. Although P-lactamases resemble elastases in the formation of an acyl-enzyme intermediate via the enzyme active-site serine, they differ in that the cooperating residues are lysine and glutamic acid for class A P-lactamases, and histidine and aspartic acid for elastases. The mechanism of action of these three types of enzymes has been supported by X-ray crystallographic determination and/or by electrospray ionization mass-spectrometry. Kinetic studies were used to decide whether a postulated intermediate lies on the reaction pathway. Application of site-directed mutagenesis has led to new insights into the mechanism of catalysis by P-lactamases. This review takes examples, mostly from P-lactam compounds developed as elastase inhibitors, to illustrate how an understanding of physico-chemical properties and an appreciation of the molecular shape and electronic properties can lead to a better insight into molecular recognition processes. The synthetic methods employed in the synthesis of lead P-lactam compounds as elastase inhibitors are also discussed.

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Ohkama-Ohtsu, Naoko, Safaa Radwan, Annita Peterson, Ping Zhao, Abdel Fattah Badr, Chengbin Xiang, and David J. Oliver. "Characterization of the extracellular γ-glutamyl transpeptidases, GGT1 and GGT2, in Arabidopsis." Plant Journal 49, no. 5 (February 2, 2007): 865–77. http://dx.doi.org/10.1111/j.1365-313x.2006.03004.x.

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Clancy, Kathleen W., Jeffrey A. Melvin, and Dewey G. McCafferty. "Erratum: Invited Review: Sortase transpeptidases: Insights into mechanism, substrate specificity, and inhibition." Biopolymers 94, no. 5 (September 17, 2010): 681. http://dx.doi.org/10.1002/bip.21529.

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Cochrane, Stephen A., and Christopher T. Lohans. "Breaking down the cell wall: Strategies for antibiotic discovery targeting bacterial transpeptidases." European Journal of Medicinal Chemistry 194 (May 2020): 112262. http://dx.doi.org/10.1016/j.ejmech.2020.112262.

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Akter, Tanzina, Mahim Chakma, Afsana Yeasmin Tanzina, Meheadi Hasan Rumi, Mst Sharmin Sultana Shimu, Md Abu Saleh, Shafi Mahmud, Saad Ahmed Sami, and Talha Bin Emran. "Curcumin Analogues as a Potential Drug against Antibiotic Resistant Protein, β-Lactamases and L, D-Transpeptidases Involved in Toxin Secretion in Salmonella typhi: A Computational Approach." BioMedInformatics 2, no. 1 (December 27, 2021): 77–100. http://dx.doi.org/10.3390/biomedinformatics2010005.

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Typhoid fever caused by the bacteria Salmonella typhi gained resistance through multidrug-resistant S. typhi strains. One of the reasons behind β-lactam antibiotic resistance is -lactamase. L, D-Transpeptidases is responsible for typhoid fever as it is involved in toxin release that results in typhoid fever in humans. A molecular modeling study of these targeted proteins was carried out by various methods, such as homology modeling, active site prediction, prediction of disease-causing regions, and by analyzing the potential inhibitory activities of curcumin analogs by targeting these proteins to overcome the antibiotic resistance. The five potent drug candidate compounds were identified to be natural ligands that can inhibit those enzymes compared to controls in our research. The binding affinity of both the Go-Y032 and NSC-43319 were found against β-lactamase was −7.8 Kcal/mol in AutoDock, whereas, in SwissDock, the binding energy was −8.15 and −8.04 Kcal/mol, respectively. On the other hand, the Cyclovalone and NSC-43319 had an equal energy of −7.60 Kcal/mol in AutoDock, whereas −7.90 and −8.01 Kcal/mol in SwissDock against L, D-Transpeptidases. After the identification of proteins, the determination of primary and secondary structures, as well as the gene producing area and homology modeling, was accomplished. The screened drug candidates were further evaluated in ADMET, and pharmacological properties along with positive drug-likeness properties were observed for these ligand molecules. However, further in vitro and in vivo experiments are required to validate these in silico data to develop novel therapeutics against antibiotic resistance.

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Haenni, Marisa, Paul A. Majcherczyk, Jean-Luc Barblan, and Philippe Moreillon. "Mutational Analysis of Class A and Class B Penicillin-Binding Proteins in Streptococcus gordonii." Antimicrobial Agents and Chemotherapy 50, no. 12 (September 25, 2006): 4062–69. http://dx.doi.org/10.1128/aac.00677-06.

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ABSTRACT High-molecular-weight (HMW) penicillin-binding proteins (PBPs) are divided into class A and class B PBPs, which are bifunctional transpeptidases/transglycosylases and monofunctional transpeptidases, respectively. We determined the sequences for the HMW PBP genes of Streptococcus gordonii, a gingivo-dental commensal related to Streptococcus pneumoniae. Five HMW PBPs were identified, including three class A (PBPs 1A, 1B, and 2A) and two class B (PBPs 2B and 2X) PBPs, by homology with those of S. pneumoniae and by radiolabeling with [3H]penicillin. Single and double deletions of each of them were achieved by allelic replacement. All could be deleted, except for PBP 2X, which was essential. Morphological alterations occurred after deletion of PBP 1A (lozenge shape), PBP 2A (separation defect and chaining), and PBP 2B (aberrant septation and premature lysis) but not PBP 1B. The muropeptide cross-link patterns remained similar in all strains, indicating that cross-linkage for one missing PBP could be replaced by others. However, PBP 1A mutants presented shorter glycan chains (by 30%) and a relative decrease (25%) in one monomer stem peptide. Growth rate and viability under aeration, hyperosmolarity, and penicillin exposure were affected primarily in PBP 2B-deleted mutants. In contrast, chain-forming PBP 2A-deleted mutants withstood better aeration, probably because they formed clusters that impaired oxygen diffusion. Double deletion could be generated with any PBP combination and resulted in more-altered mutants. Thus, single deletion of four of the five HMW genes had a detectable effect on the bacterial morphology and/or physiology, and only PBP 1B seemed redundant a priori.

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Straume, Daniel, Katarzyna Wiaroslawa Piechowiak, Silje Olsen, Gro Anita Stamsås, Kari Helene Berg, Morten Kjos, Maria Victoria Heggenhougen, Martín Alcorlo, Juan A. Hermoso, and Leiv Sigve Håvarstein. "Class A PBPs have a distinct and unique role in the construction of the pneumococcal cell wall." Proceedings of the National Academy of Sciences 117, no. 11 (March 2, 2020): 6129–38. http://dx.doi.org/10.1073/pnas.1917820117.

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In oval-shapedStreptococcus pneumoniae, septal and longitudinal peptidoglycan syntheses are performed by independent functional complexes: the divisome and the elongasome. Penicillin-binding proteins (PBPs) were long considered the key peptidoglycan-synthesizing enzymes in these complexes. Among these were the bifunctional class A PBPs, which are both glycosyltransferases and transpeptidases, and monofunctional class B PBPs with only transpeptidase activity. Recently, however, it was established that the monofunctional class B PBPs work together with transmembrane glycosyltransferases (FtsW and RodA) from the shape, elongation, division, and sporulation (SEDS) family to make up the core peptidoglycan-synthesizing machineries within the pneumococcal divisome (FtsW/PBP2x) and elongasome (RodA/PBP2b). The function of class A PBPs is therefore now an open question. Here we utilize the peptidoglycan hydrolase CbpD that targets the septum ofS. pneumoniaecells to show that class A PBPs have an autonomous role during pneumococcal cell wall synthesis. Using assays to specifically inhibit the function of PBP2x and FtsW, we demonstrate that CbpD attacks nascent peptidoglycan synthesized by the divisome. Notably, class A PBPs could process this nascent peptidoglycan from a CbpD-sensitive to a CbpD-resistant form. The class A PBP-mediated processing was independent of divisome and elongasome activities. Class A PBPs thus constitute an autonomous functional entity which processes recently formed peptidoglycan synthesized by FtsW/PBP2×. Our results support a model in which mature pneumococcal peptidoglycan is synthesized by three functional entities, the divisome, the elongasome, and bifunctional PBPs. The latter modify existing peptidoglycan but are probably not involved in primary peptidoglycan synthesis.

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Rice, Louis B., Lenore L. Carias, Susan Rudin, Rebecca Hutton, Steven Marshall, Medhat Hassan, Nathalie Josseaume, Lionel Dubost, Arul Marie, and Michel Arthur. "Role of Class A Penicillin-Binding Proteins in the Expression of β-Lactam Resistance in Enterococcus faecium." Journal of Bacteriology 191, no. 11 (March 20, 2009): 3649–56. http://dx.doi.org/10.1128/jb.01834-08.

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ABSTRACT Peptidoglycan is polymerized by monofunctional d,d-transpeptidases belonging to class B penicillin-binding proteins (PBPs) and monofunctional glycosyltransferases and by bifunctional enzymes that combine both activities (class A PBPs). Three genes encoding putative class A PBPs (pbpF, pbpZ, and ponA) were deleted from the chromosome of Enterococcus faecium D344R in all possible combinations in order to identify the glycosyltransferases that cooperate with low-affinity class B Pbp5 for synthesis of peptidoglycan in the presence of β-lactam antibiotics. The viability of the triple mutant indicated that glycan strands can be polymerized independently from class A PBPs by an unknown glycosyltranferase. The susceptibility of the ΔpbpF ΔponA mutant and triple mutants to extended spectrum cephalosporins (ceftriaxone and cefepime) identified either PbpF or PonA as essential partners of Pbp5 for peptidoglycan polymerization in the presence of the drugs. Mass spectrometry analysis of peptidoglycan structure showed that loss of PonA and PbpF activity led to a minor decrease in the extent of peptidoglycan cross-linking by the remaining PBPs without any detectable compensatory increase in the participation of the l,d-transpeptidase in peptidoglycan synthesis. Optical density measurements and electron microscopy analyses showed that the ΔpbpF ΔponA mutant underwent increased stationary-phase autolysis compared to the parental strain. Unexpectedly, deletion of the class A pbp genes revealed dissociation between the expression of resistance to cephalosporins and penicillins, although the production of Pbp5 was required for resistance to both classes of drugs. Thus, susceptibility of Pbp5-mediated peptidoglycan cross-linking to different β-lactam antibiotics differed as a function of its partner glycosyltransferase.

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Magnet, Sophie, Ana Arbeloa, Jean-Luc Mainardi, Jean-Emmanuel Hugonnet, Martine Fourgeaud, Lionel Dubost, Arul Marie, et al. "Specificity of L,D-Transpeptidases from Gram-positive Bacteria Producing Different Peptidoglycan Chemotypes." Journal of Biological Chemistry 282, no. 18 (February 20, 2007): 13151–59. http://dx.doi.org/10.1074/jbc.m610911200.

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35

Lavollay, M., M. Fourgeaud, J. L. Herrmann, L. Dubost, A. Marie, L. Gutmann, M. Arthur, and J. L. Mainardi. "The Peptidoglycan of Mycobacterium abscessus Is Predominantly Cross-Linked by L,D-Transpeptidases." Journal of Bacteriology 193, no. 3 (November 19, 2010): 778–82. http://dx.doi.org/10.1128/jb.00606-10.

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36

Navratna, Vikas, Savitha Nadig, Varun Sood, K. Prasad, Gayathri Arakere, and B. Gopal. "Molecular Basis for the Role of Staphylococcus aureus Penicillin Binding Protein 4 in Antimicrobial Resistance." Journal of Bacteriology 192, no. 1 (October 23, 2009): 134–44. http://dx.doi.org/10.1128/jb.00822-09.

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ABSTRACT Penicillin binding proteins (PBPs) are membrane-associated proteins that catalyze the final step of murein biosynthesis. These proteins function as either transpeptidases or carboxypeptidases and in a few cases demonstrate transglycosylase activity. Both transpeptidase and carboxypeptidase activities of PBPs occur at the d-Ala-d-Ala terminus of a murein precursor containing a disaccharide pentapeptide comprising N-acetylglucosamine and N-acetyl-muramic acid-l-Ala-d-Glu-l-Lys-d-Ala-d-Ala. β-Lactam antibiotics inhibit these enzymes by competing with the pentapeptide precursor for binding to the active site of the enzyme. Here we describe the crystal structure, biochemical characteristics, and expression profile of PBP4, a low-molecular-mass PBP from Staphylococcus aureus strain COL. The crystal structures of PBP4-antibiotic complexes reported here were determined by molecular replacement, using the atomic coordinates deposited by the New York Structural Genomics Consortium. While the pbp4 gene is not essential for the viability of S. aureus, the knockout phenotype of this gene is characterized by a marked reduction in cross-linked muropeptide and increased vancomycin resistance. Unlike other PBPs, we note that expression of PBP4 was not substantially altered under different experimental conditions, nor did it change across representative hospital- or community-associated strains of S. aureus that were examined. In vitro data on purified recombinant S. aureus PBP4 suggest that it is a β-lactamase and is not trapped as an acyl intermediate with β-lactam antibiotics. Put together, the expression analysis and biochemical features of PBP4 provide a framework for understanding the function of this protein in S. aureus and its role in antimicrobial resistance.

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Martin, Melinda Neal, and Janet P. Slovin. "Purified γ-Glutamyl Transpeptidases from Tomato Exhibit High Affinity for Glutathione and GlutathioneS-Conjugates." Plant Physiology 122, no. 4 (April 1, 2000): 1417–26. http://dx.doi.org/10.1104/pp.122.4.1417.

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Barry, Clifton, David Kastrinsky, Pradeep Kumar, and Gwendolyn Marriner. "A Convergent Synthesis of Chiral Diaminopimelic Acid Derived Substrates for Mycobacterial l,d-Transpeptidases." Synthesis 44, no. 19 (August 29, 2012): 3043–48. http://dx.doi.org/10.1055/s-0032-1316774.

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Sibinelli-Sousa, Stephanie, Julia T. Hespanhol, Gianlucca G. Nicastro, Bruno Y. Matsuyama, Stephane Mesnage, Ankur Patel, Robson F. de Souza, Cristiane R. Guzzo, and Ethel Bayer-Santos. "A Family of T6SS Antibacterial Effectors Related to l,d-Transpeptidases Targets the Peptidoglycan." Cell Reports 31, no. 12 (June 2020): 107813. http://dx.doi.org/10.1016/j.celrep.2020.107813.

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40

Khare, Baldeep, Alexandra Samal, Krishnan Vengadesan, K. R. Rajashankar, Xin Ma, I.-Hsiu Huang, Hung Ton-That, and Sthanam V. L. Narayana. "Preliminary crystallographic study of theStreptococcus agalactiaesortases, sortase A and sortase C1." Acta Crystallographica Section F Structural Biology and Crystallization Communications 66, no. 9 (August 28, 2010): 1096–100. http://dx.doi.org/10.1107/s1744309110031106.

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Sortases are cysteine transpeptidases that are essential for the assembly and anchoring of cell-surface adhesins in Gram-positive bacteria. InStreptococcus agalactiae(GBS), the pilin-specific sortase SrtC1 catalyzes the polymerization of pilins encoded by pilus island 1 (PI-1) and the housekeeping sortase SrtA is necessary for cell-wall anchoring of the resulting pilus polymers. These sortases are known to utilize different substrates for pilus polymerization and cell-wall anchoring; however, the structural correlates that dictate their substrate specificity have not yet been clearly defined. This report presents the expression, purification and crystallization of SrtC1 (SAG0647) and SrtA (SAG0961) fromS. agalactiaestrain 2603V/R. The GBS SrtC1 has been crystallized in three crystal forms and the GBS SrtA has been crystallized in one crystal form.

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Magnet, Sophie, Samuel Bellais, Lionel Dubost, Martine Fourgeaud, Jean-Luc Mainardi, Sébastien Petit-Frère, Arul Marie, Dominique Mengin-Lecreulx, Michel Arthur, and Laurent Gutmann. "Identification of the l,d-Transpeptidases Responsible for Attachment of the Braun Lipoprotein to Escherichia coli Peptidoglycan." Journal of Bacteriology 189, no. 10 (March 16, 2007): 3927–31. http://dx.doi.org/10.1128/jb.00084-07.

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ABSTRACT The l,d-transpeptidase Ldtfm catalyzes peptidoglycan cross-linking in β-lactam-resistant mutant strains of Enterococcus faecium. Here, we show that in Escherichia coli Ldtfm homologues are responsible for the attachment of the Braun lipoprotein to murein, indicating that evolutionarily related domains have been tailored to use muropeptides or proteins as acyl acceptors in the l,d-transpeptidation reaction.

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SCHWIMMER, SIGMUND, and SANDRA J. AUSTIN. "ENHANCEMENT OF PYRUVIC ACID RELEASE AND FLAVOR IN DEHYDRATED ALLIUM POWDERS BY GAMMA GLUTAMYL TRANSPEPTIDASES." Journal of Food Science 36, no. 7 (June 28, 2008): 1081–85. http://dx.doi.org/10.1111/j.1365-2621.1971.tb03351.x.

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Ngadjeua, Flora, Emmanuelle Braud, Saidbakhrom Saidjalolov, Laura Iannazzo, Dirk Schnappinger, Sabine Ehrt, Jean-Emmanuel Hugonnet, et al. "Critical Impact of Peptidoglycan Precursor Amidation on the Activity ofl,d-Transpeptidases fromEnterococcus faeciumandMycobacterium tuberculosis." Chemistry - A European Journal 24, no. 22 (February 21, 2018): 5743–47. http://dx.doi.org/10.1002/chem.201706082.

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Mazzella, L. J., and R. F. Pratt. "Effect of the 3′-leaving group on turnover of cephem antibiotics by a class C β-lactamase." Biochemical Journal 259, no. 1 (April 1, 1989): 255–60. http://dx.doi.org/10.1042/bj2590255.

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It has been previously demonstrated for class A beta-lactamases and the DD-peptidase of Streptomyces R61 that the presence of a leaving group at the 3′-position of a cephalosporin can lead to the generation of more-inert acyl-enzyme intermediates than from cephalosporins lacking such a leaving group, and thus to beta-lactamase inhibitors and potentially better antibiotics. In the present work we extend this result to a class C beta-lactamase, that of Enterobacter cloacae P99. The effect is not seen with first-generation cephalosporins, since here deacylation generally seems faster than elimination of the leaving group, but it does clearly appear with cephamycins and third-generation cephalosporins. The structural and/or mechanistic features of the active site giving rise to this phenomenon may thus be common to all serine beta-lactamases and transpeptidases.

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Meng, Xiangyu, Danyang Huang, Qing Zhou, Fan Ji, Xin Tan, Jianli Wang, and Xiaoyuan Wang. "The Influence of Outer Membrane Protein on Ampicillin Resistance of Vibrio parahaemolyticus." Canadian Journal of Infectious Diseases and Medical Microbiology 2023 (January 13, 2023): 1–13. http://dx.doi.org/10.1155/2023/8079091.

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The antibiotic resistance of the food-borne pathogen Vibrio parahaemolyticus has attracted researchers’ attention in recent years, but its molecular mechanism remains poorly understood. In this study, 7 genes encoding outer membrane proteins (OMPs) were individually deleted in V. parahaemolyticus ATCC33846, and the resistance of these 7 mutants to 14 antibiotics was investigated. The results revealed that the resistance of the 7 mutants to ampicillin was significantly increased. Further exploration of 20-gene transcription changes by real time-qPCR (RT-qPCR) demonstrated that the higher ampicillin resistance might be attributed to the expression of β-lactamase and reduced peptidoglycan (PG) synthesis activity through reduced transcription of penicillin-binding proteins (PBPs), increased transcription of l,d-transpeptidases, downregulated d,d-carboxypeptidase, and alanine deficiency. This study provides a new perspective on ampicillin resistance in OMP mutants with respect to PG synthesis.

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Lin, Huibin, Liyuan Lin, Yahui Du, Juan Gao, Chaoyong Yang, and Wei Wang. "Biodistributions of l,d-Transpeptidases in Gut Microbiota Revealed by In Vivo Labeling with Peptidoglycan Analogs." ACS Chemical Biology 16, no. 7 (June 29, 2021): 1164–71. http://dx.doi.org/10.1021/acschembio.1c00346.

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47

Peters, Katharina, Manuel Pazos, Zainab Edoo, Jean-Emmanuel Hugonnet, Alessandra M. Martorana, Alessandra Polissi, Michael S. VanNieuwenhze, Michel Arthur, and Waldemar Vollmer. "Copper inhibits peptidoglycan LD-transpeptidases suppressing β-lactam resistance due to bypass of penicillin-binding proteins." Proceedings of the National Academy of Sciences 115, no. 42 (October 1, 2018): 10786–91. http://dx.doi.org/10.1073/pnas.1809285115.

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The peptidoglycan (PG) layer stabilizes the bacterial cell envelope to maintain the integrity and shape of the cell. Penicillin-binding proteins (PBPs) synthesize essential 4–3 cross-links in PG and are inhibited by β-lactam antibiotics. Some clinical isolates and laboratory strains ofEnterococcus faeciumandEscherichia coliachieve high-level β-lactam resistance by utilizing β-lactam–insensitive LD-transpeptidases (LDTs) to produce exclusively 3–3 cross-links in PG, bypassing the PBPs. InE. coli, other LDTs covalently attach the lipoprotein Lpp to PG to stabilize the envelope and maintain the permeability barrier function of the outermembrane. Here we show that subminimal inhibitory concentration of copper chloride sensitizesE. colicells to sodium dodecyl sulfate and impair survival upon LPS transport stress, indicating reduced cell envelope robustness. Cells grown in the presence of copper chloride lacked 3–3 cross-links in PG and displayed reduced covalent attachment of Braun’s lipoprotein and reduced incorporation of a fluorescentd-amino acid, suggesting inhibition of LDTs. Copper dramatically decreased the minimal inhibitory concentration of ampicillin inE. coliandE. faeciumstrains with a resistance mechanism relying on LDTs and inhibited purified LDTs at submillimolar concentrations. Hence, our work reveals how copper affects bacterial cell envelope stability and counteracts LDT-mediated β-lactam resistance.

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Lohans, Christopher T., H. T. Henry Chan, Tika R. Malla, Kiran Kumar, Jos J. A. G. Kamps, Darius J. B. McArdle, Emma van Groesen, et al. "Non-Hydrolytic β-Lactam Antibiotic Fragmentation by l,d -Transpeptidases and Serine β-Lactamase Cysteine Variants." Angewandte Chemie 131, no. 7 (January 21, 2019): 2012–16. http://dx.doi.org/10.1002/ange.201809424.

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Lohans, Christopher T., H. T. Henry Chan, Tika R. Malla, Kiran Kumar, Jos J. A. G. Kamps, Darius J. B. McArdle, Emma van Groesen, et al. "Non-Hydrolytic β-Lactam Antibiotic Fragmentation by l,d -Transpeptidases and Serine β-Lactamase Cysteine Variants." Angewandte Chemie International Edition 58, no. 7 (January 21, 2019): 1990–94. http://dx.doi.org/10.1002/anie.201809424.

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Suryadinata, Randy, Shane A. Seabrook, Timothy E. Adams, Stewart D. Nuttall, and Thomas S. Peat. "Structural and biochemical analyses of aClostridium perfringenssortase D transpeptidase." Acta Crystallographica Section D Biological Crystallography 71, no. 7 (June 30, 2015): 1505–13. http://dx.doi.org/10.1107/s1399004715009219.

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The assembly and anchorage of various pathogenic proteins on the surface of Gram-positive bacteria is mediated by the sortase family of enzymes. These cysteine transpeptidases catalyze a unique sorting signal motif located at the C-terminus of their target substrate and promote the covalent attachment of these proteins onto an amino nucleophile located on another protein or on the bacterial cell wall. Each of the six distinct classes of sortases displays a unique biological role, with sequential activation of multiple sortases often observed in many Gram-positive bacteria to decorate their peptidoglycans. Less is known about the members of the class D family of sortases (SrtD), but they have a suggested role in spore formation in an oxygen-limiting environment. Here, the crystal structure of the SrtD enzyme fromClostridium perfringenswas determined at 1.99 Å resolution. Comparative analysis of theC. perfringensSrtD structure reveals the typical eight-stranded β-barrel fold observed in all other known sortases, along with the conserved catalytic triad consisting of cysteine, histidine and arginine residues. Biochemical approaches further reveal the specifics of the SrtD catalytic activityin vitro, with a significant preference for the LPQTGS sorting motif. Additionally, the catalytic activity of SrtD is most efficient at 316 K and can be further improved in the presence of magnesium cations. SinceC. perfringensspores are heat-resistant and lead to foodborne illnesses, characterization of the spore-promoting sortase SrtD may lead to the development of new antimicrobial agents.

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