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3452 KiB

Open AccessArticle

Bulgecin A: The Key to a Broad‐Spectrum Inhibitor That Targets Lytic Transglycosylases

by Allison H. Williams, Richard Wheeler, Constance Thiriau, Ahmed Haouz, Muhamed‐Kheir Taha and Ivo G. Boneca

Antibiotics 2017, 6(1), 8; https://doi.org/10.3390/antibiotics6010008 - 22 Feb 2017

Cited by 28 | Viewed by 7073

Abstract

Lytic transglycosylases (Lts) are involved in recycling, cell division, and metabolism of the peptidoglycan. They have been understudied for their usefulness as potential antibacterial targets due to their high redundancy in Gram‐negative bacteria. Bulgecin A is an O‐sulphonated glycopeptide that targets primarily soluble [...] Read more.

Lytic transglycosylases (Lts) are involved in recycling, cell division, and metabolism of the peptidoglycan. They have been understudied for their usefulness as potential antibacterial targets due to their high redundancy in Gram‐negative bacteria. Bulgecin A is an O‐sulphonated glycopeptide that targets primarily soluble lytic tranglycosylases (Slt). It has been shown that bulgecin A increases the efficacy of β‐lactams that target penicillin bindings proteins (PBPs). Here, we present the high‐resolution crystal structure of LtgA from Neisseria meningitidis strain MC58, a membrane bound homolog of Escherichia coli Slt, in complex with bulgecin A. The LtgA‐bulgecin A complex reveals the mechanism of inhibition by bulgecin A at near atomic resolution. We further demonstrate that bulgecin A is not only a potent inhibitor of LtgA, but most importantly, it restores the efficacy of β‐lactam antibiotics in strains of N. meningitidis and Neisseria gonorrhoeae that have reduced susceptibility to β‐lactams. This is particularly relevant for N. gonorrhoeae where no vaccines are available. This work illustrates how best to target dangerous pathogens using a multiple drug target approach, a new and alternative approach to fighting antibiotic resistance. Full article

(This article belongs to the Special Issue Bacterial Cell Wall as Antimicrobial Target)

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2535 KiB

Open AccessArticle

Pectocin M1 (PcaM1) Inhibits Escherichia coli Cell Growth and Peptidoglycan Biosynthesis through Periplasmic Expression

by Dimitri Chérier, Sean Giacomucci, Delphine Patin, Ahmed Bouhss, Thierry Touzé, Didier Blanot, Dominique Mengin-Lecreulx and Hélène Barreteau

Antibiotics 2016, 5(4), 36; https://doi.org/10.3390/antibiotics5040036 - 08 Oct 2016

Cited by 5 | Viewed by 5575

Abstract

Colicins are bacterial toxins produced by some Escherichia coli strains. They exhibit either enzymatic or pore-forming activity towards a very limited number of bacterial species, due to the high specificity of their reception and translocation systems. Yet, we succeeded in making the colicin [...] Read more.

Colicins are bacterial toxins produced by some Escherichia coli strains. They exhibit either enzymatic or pore-forming activity towards a very limited number of bacterial species, due to the high specificity of their reception and translocation systems. Yet, we succeeded in making the colicin M homologue from Pectobacterium carotovorum, pectocin M1 (PcaM1), capable of inhibiting E. coli cell growth by bypassing these reception and translocation steps. This goal was achieved through periplasmic expression of this pectocin. Indeed, when appropriately addressed to the periplasm of E. coli, this pectocin could exert its deleterious effects, i.e., the enzymatic degradation of the peptidoglycan lipid II precursor, which resulted in the arrest of the biosynthesis of this essential cell wall polymer, dramatic morphological changes and, ultimately, cell lysis. This result leads to the conclusion that colicin M and its various orthologues constitute powerful antibacterial molecules able to kill any kind of bacterium, once they can reach their lipid II target. They thus have to be seriously considered as promising alternatives to antibiotics. Full article

(This article belongs to the Special Issue Bacterial Cell Wall as Antimicrobial Target)

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Open AccessArticle

The Peptidoglycan Pattern of Staphylococcus carnosus TM300—Detailed Analysis and Variations Due to Genetic and Metabolic Influences

by Julia Deibert, Daniel Kühner, Mark Stahl, Elif Koeksoy and Ute Bertsche

Antibiotics 2016, 5(4), 33; https://doi.org/10.3390/antibiotics5040033 - 23 Sep 2016

Cited by 4 | Viewed by 7023

Abstract

The Gram-positive bacterium Staphylococcus carnosus (S. carnosus) TM300 is an apathogenic staphylococcal species commonly used in meat starter cultures. As with all Gram-positive bacteria, its cytoplasmic membrane is surrounded by a thick peptidoglycan (PGN) or murein sacculus consisting of several layers [...] Read more.

The Gram-positive bacterium Staphylococcus carnosus (S. carnosus) TM300 is an apathogenic staphylococcal species commonly used in meat starter cultures. As with all Gram-positive bacteria, its cytoplasmic membrane is surrounded by a thick peptidoglycan (PGN) or murein sacculus consisting of several layers of glycan strands cross-linked by peptides. In contrast to pathogenic staphylococci, mainly Staphylococcus aureus (S. aureus), the chemical composition of S. carnosus PGN is not well studied so far. UPLC/MS analysis of enzymatically digested S. carnosus TM300 PGN revealed substantial differences in its composition compared to the known pattern of S. aureus. While in S. aureus the uncross-linked stem peptide consists of a pentapeptide, in S. carnosus, this part of the PGN is shortened to tripeptides. Furthermore, we found the PGN composition to vary when cells were incubated under certain conditions. The collective overproduction of HlyD, FtsE and FtsX—a putative protein complex interacting with penicillin-binding protein 2 (PBP2)—caused the reappearance of classical penta stem peptides. In addition, under high sugar conditions, tetra stem peptides occur due to overflow metabolism. This indicates that S. carnosus TM300 cells adapt to various conditions by modification of their PGN. Full article

(This article belongs to the Special Issue Bacterial Cell Wall as Antimicrobial Target)

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2871 KiB

Open AccessArticle

Identification of a Fragment-Based Scaffold that Inhibits the Glycosyltransferase WaaG from Escherichia coli

by Claudio Muheim, Amin Bakali, Olof Engström, Åke Wieslander, Daniel O. Daley and Göran Widmalm

Antibiotics 2016, 5(1), 10; https://doi.org/10.3390/antibiotics5010010 - 28 Jan 2016

Cited by 5 | Viewed by 5989

Abstract

WaaG is a glycosyltransferase that is involved in the biosynthesis of lipopolysaccharide in Gram-negative bacteria. Inhibitors of WaaG are highly sought after as they could be used to inhibit the biosynthesis of the core region of lipopolysaccharide, which would improve the uptake of [...] Read more.

WaaG is a glycosyltransferase that is involved in the biosynthesis of lipopolysaccharide in Gram-negative bacteria. Inhibitors of WaaG are highly sought after as they could be used to inhibit the biosynthesis of the core region of lipopolysaccharide, which would improve the uptake of antibiotics. Herein, we establish an activity assay for WaaG using ¹⁴C-labeled UDP-glucose and LPS purified from a ∆waaG strain of Escherichia coli. We noted that addition of the lipids phosphatidylglycerol (PG) and cardiolipin (CL), as well as the detergent 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS) increased activity. We then use the assay to determine if three molecular scaffolds, which bind to WaaG, could inhibit its activity in vitro. We show that 4-(2-amino-1,3-thiazol-4-yl)phenol inhibits WaaG (IC₅₀ 1.0 mM), but that the other scaffolds do not. This study represents an important step towards an inhibitor of WaaG by fragment-based lead discovery. Full article

(This article belongs to the Special Issue Bacterial Cell Wall as Antimicrobial Target)

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Review

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Open AccessReview

Resistance to β-Lactams in Neisseria ssp Due to Chromosomally Encoded Penicillin-Binding Proteins

by André Zapun, Cécile Morlot and Muhamed-Kheir Taha

Antibiotics 2016, 5(4), 35; https://doi.org/10.3390/antibiotics5040035 - 28 Sep 2016

Cited by 39 | Viewed by 7717

Abstract

Neisseria meningitidis and Neisseria gonorrhoeae are human pathogens that cause a variety of life-threatening systemic and local infections, such as meningitis or gonorrhoea. The treatment of such infection is becoming more difficult due to antibiotic resistance. The focus of this review is on [...] Read more.

Neisseria meningitidis and Neisseria gonorrhoeae are human pathogens that cause a variety of life-threatening systemic and local infections, such as meningitis or gonorrhoea. The treatment of such infection is becoming more difficult due to antibiotic resistance. The focus of this review is on the mechanism of reduced susceptibility to penicillin and other β-lactams due to the modification of chromosomally encoded penicillin-binding proteins (PBP), in particular PBP2 encoded by the penA gene. The variety of penA alleles and resulting variant PBP2 enzymes is described and the important amino acid substitutions are presented and discussed in a structural context. Full article

(This article belongs to the Special Issue Bacterial Cell Wall as Antimicrobial Target)

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Open AccessReview

The Membrane Steps of Bacterial Cell Wall Synthesis as Antibiotic Targets

by Yao Liu and Eefjan Breukink

Antibiotics 2016, 5(3), 28; https://doi.org/10.3390/antibiotics5030028 - 26 Aug 2016

Cited by 78 | Viewed by 29452

Abstract

Peptidoglycan is the major component of the cell envelope of virtually all bacteria. It has structural roles and acts as a selective sieve for molecules from the outer environment. Peptidoglycan synthesis is therefore one of the most important biogenesis pathways in bacteria and [...] Read more.

Peptidoglycan is the major component of the cell envelope of virtually all bacteria. It has structural roles and acts as a selective sieve for molecules from the outer environment. Peptidoglycan synthesis is therefore one of the most important biogenesis pathways in bacteria and has been studied extensively over the last twenty years. The pathway starts in the cytoplasm, continues in the cytoplasmic membrane and finishes in the periplasmic space, where the precursor is polymerized into the peptidoglycan layer. A number of proteins involved in this pathway, such as the Mur enzymes and the penicillin binding proteins (PBPs), have been studied and regarded as good targets for antibiotics. The present review focuses on the membrane steps of peptidoglycan synthesis that involve two enzymes, MraY and MurG, the inhibitors of these enzymes and the inhibition mechanisms. We also discuss the challenges of targeting these two cytoplasmic membrane (associated) proteins in bacterial cells and the perspectives on how to overcome the issues. Full article

(This article belongs to the Special Issue Bacterial Cell Wall as Antimicrobial Target)

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Open AccessReview

Choline Binding Proteins from Streptococcus pneumoniae: A Dual Role as Enzybiotics and Targets for the Design of New Antimicrobials

by Beatriz Maestro and Jesús M. Sanz

Antibiotics 2016, 5(2), 21; https://doi.org/10.3390/antibiotics5020021 - 14 Jun 2016

Cited by 57 | Viewed by 11945

Abstract

Streptococcus pneumoniae (pneumococcus) is an important pathogen responsible for acute invasive and non-invasive infections such as meningitis, sepsis and otitis media, being the major cause of community-acquired pneumonia. The fight against pneumococcus is currently hampered both by insufficient vaccine coverage and by rising [...] Read more.

Streptococcus pneumoniae (pneumococcus) is an important pathogen responsible for acute invasive and non-invasive infections such as meningitis, sepsis and otitis media, being the major cause of community-acquired pneumonia. The fight against pneumococcus is currently hampered both by insufficient vaccine coverage and by rising antimicrobial resistances to traditional antibiotics, making necessary the research on novel targets. Choline binding proteins (CBPs) are a family of polypeptides found in pneumococcus and related species, as well as in some of their associated bacteriophages. They are characterized by a structural organization in two modules: a functional module (FM), and a choline-binding module (CBM) that anchors the protein to the choline residues present in the cell wall through non-covalent interactions. Pneumococcal CBPs include cell wall hydrolases, adhesins and other virulence factors, all playing relevant physiological roles for bacterial viability and virulence. Moreover, many pneumococcal phages also make use of hydrolytic CBPs to fulfill their infectivity cycle. Consequently, CBPs may play a dual role for the development of novel antipneumococcal drugs, both as targets for inhibitors of their binding to the cell wall and as active cell lytic agents (enzybiotics). In this article, we review the current state of knowledge about host- and phage-encoded pneumococcal CBPs, with a special focus on structural issues, together with their perspectives for effective anti-infectious treatments. Full article

(This article belongs to the Special Issue Bacterial Cell Wall as Antimicrobial Target)

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Open AccessReview

Structural Insights into Protein-Protein Interactions Involved in Bacterial Cell Wall Biogenesis

by Federica Laddomada, Mayara M. Miyachiro and Andréa Dessen

Antibiotics 2016, 5(2), 14; https://doi.org/10.3390/antibiotics5020014 - 28 Apr 2016

Cited by 25 | Viewed by 8925

Abstract

The bacterial cell wall is essential for survival, and proteins that participate in its biosynthesis have been the targets of antibiotic development efforts for decades. The biosynthesis of its main component, the peptidoglycan, involves the coordinated action of proteins that are involved in [...] Read more.

The bacterial cell wall is essential for survival, and proteins that participate in its biosynthesis have been the targets of antibiotic development efforts for decades. The biosynthesis of its main component, the peptidoglycan, involves the coordinated action of proteins that are involved in multi-member complexes which are essential for cell division (the “divisome”) and/or cell wall elongation (the “elongasome”), in the case of rod-shaped cells. Our knowledge regarding these interactions has greatly benefitted from the visualization of different aspects of the bacterial cell wall and its cytoskeleton by cryoelectron microscopy and tomography, as well as genetic and biochemical screens that have complemented information from high resolution crystal structures of protein complexes involved in divisome or elongasome formation. This review summarizes structural and functional aspects of protein complexes involved in the cytoplasmic and membrane-related steps of peptidoglycan biosynthesis, with a particular focus on protein-protein interactions whereby disruption could lead to the development of novel antibacterial strategies. Full article

(This article belongs to the Special Issue Bacterial Cell Wall as Antimicrobial Target)

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Open AccessReview

Glycosyltransferases and Transpeptidases/Penicillin-Binding Proteins: Valuable Targets for New Antibacterials

by Eric Sauvage and Mohammed Terrak

Antibiotics 2016, 5(1), 12; https://doi.org/10.3390/antibiotics5010012 - 17 Feb 2016

Cited by 82 | Viewed by 23649

Abstract

Peptidoglycan (PG) is an essential macromolecular sacculus surrounding most bacteria. It is assembled by the glycosyltransferase (GT) and transpeptidase (TP) activities of multimodular penicillin-binding proteins (PBPs) within multiprotein complex machineries. Both activities are essential for the synthesis of a functional stress-bearing PG shell. [...] Read more.

Peptidoglycan (PG) is an essential macromolecular sacculus surrounding most bacteria. It is assembled by the glycosyltransferase (GT) and transpeptidase (TP) activities of multimodular penicillin-binding proteins (PBPs) within multiprotein complex machineries. Both activities are essential for the synthesis of a functional stress-bearing PG shell. Although good progress has been made in terms of the functional and structural understanding of GT, finding a clinically useful antibiotic against them has been challenging until now. In contrast, the TP/PBP module has been successfully targeted by β-lactam derivatives, but the extensive use of these antibiotics has selected resistant bacterial strains that employ a wide variety of mechanisms to escape the lethal action of these antibiotics. In addition to traditional β-lactams, other classes of molecules (non-β-lactams) that inhibit PBPs are now emerging, opening new perspectives for tackling the resistance problem while taking advantage of these valuable targets, for which a wealth of structural and functional knowledge has been accumulated. The overall evidence shows that PBPs are part of multiprotein machineries whose activities are modulated by cofactors. Perturbation of these systems could lead to lethal effects. Developing screening strategies to take advantage of these mechanisms could lead to new inhibitors of PG assembly. In this paper, we present a general background on the GTs and TPs/PBPs, a survey of recent issues of bacterial resistance and a review of recent works describing new inhibitors of these enzymes. Full article

(This article belongs to the Special Issue Bacterial Cell Wall as Antimicrobial Target)

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5481 KiB

Open AccessReview

Core Steps of Membrane-Bound Peptidoglycan Biosynthesis: Recent Advances, Insight and Opportunities

by Alvin C. K. Teo and David I. Roper

Antibiotics 2015, 4(4), 495-520; https://doi.org/10.3390/antibiotics4040495 - 03 Nov 2015

Cited by 30 | Viewed by 13526

Abstract

We are entering an era where the efficacy of current antibiotics is declining, due to the development and widespread dispersion of antibiotic resistance mechanisms. These factors highlight the need for novel antimicrobial discovery. A large number of antimicrobial natural products elicit their effect [...] Read more.

We are entering an era where the efficacy of current antibiotics is declining, due to the development and widespread dispersion of antibiotic resistance mechanisms. These factors highlight the need for novel antimicrobial discovery. A large number of antimicrobial natural products elicit their effect by directly targeting discrete areas of peptidoglycan metabolism. Many such natural products bind directly to the essential cell wall precursor Lipid II and its metabolites, i.e., preventing the utlisation of vital substrates by direct binding rather than inhibiting the metabolising enzymes themselves. Concurrently, there has been an increase in the knowledge surrounding the proteins essential to the metabolism of Lipid II at and across the cytoplasmic membrane. In this review, we draw these elements together and look to future antimicrobial opportunities in this area. Full article

(This article belongs to the Special Issue Bacterial Cell Wall as Antimicrobial Target)

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