Peptidoglycan biosynthesis machinery: a rich source of drug targets.

doi:10.3109/07388551.2010.525498

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Peptidoglycan biosynthesis machinery: a rich source of drug targets.

Journal Article•DOI•

Peptidoglycan biosynthesis machinery: a rich source of drug targets.

Ankur Gautam¹, Rajan Vyas¹, Rupinder Tewari¹•Institutions (1)

Panjab University, Chandigarh¹

11 Nov 2011-Critical Reviews in Biotechnology (Taylor & Francis)-Vol. 31, Iss: 4, pp 295-336

TL;DR: This review discusses the mechanistic and structural properties of the PG biosynthetic enzymes and inhibitors developed in the last decade.

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Abstract: The range of antibiotic therapy for the control of bacterial infections is becoming increasingly limited because of the rapid rise in multidrug resistance in clinical bacterial isolates. A few diseases, such as tuberculosis, which were once thought to be under control, have re-emerged as serious health threats. These problems have resulted in intensified research to look for new inhibitors for bacterial pathogens. Of late, the peptidoglycan (PG) layer, the most important component of the bacterial cell wall has been the subject of drug targeting because, first, it is essential for the survivability of eubacteria and secondly, it is absent in humans. The last decade has seen tremendous inputs in deciphering the 3-D structures of the PG biosynthetic enzymes. Many inhibitors against these enzymes have been developed using virtual and high throughput screening techniques. This review discusses the mechanistic and structural properties of the PG biosynthetic enzymes and inhibitors developed in the last decade.

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Journal Article•DOI•

Innate immune recognition of microbial cell wall components and microbial strategies to evade such recognitions.

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V. Sukhithasri¹, N. Nisha¹, Lalitha Biswas¹, V. Anil Kumar¹, Raja Biswas¹ - Show less +1 more•Institutions (1)

Amrita Institute of Medical Sciences and Research Centre¹

25 Aug 2013-Microbiological Research

TL;DR: This review focuses on the recent advances in understanding the role of bacterial and fungal cell wall in their innate immune recognition and evasion strategies.

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137 citations

Cites background from "Peptidoglycan biosynthesis machiner..."

...The lipid-II (bactoprenol linked disaccharide pentapeptide) is then transported to the outer surface of the cytoplasmic membrane where it gets incorporated into the growing PG chain through polymerization reactions catalyzed by transpeptidases and transglycosylases (Brotz et al., 1998; Gautam et al., 2011)....
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...…(bactoprenol linked disaccharide pentapeptide) is then transported to the outer surface of the cytoplasmic membrane where it gets incorporated into the growing PG chain through polymerization reactions catalyzed by transpeptidases and transglycosylases (Brotz et al., 1998; Gautam et al., 2011)....
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Journal Article•DOI•

Inhibitors of the peptidoglycan biosynthesis enzymes MurA-F

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Martina Hrast¹, Izidor Sosič¹, Roman Šink¹, Stanislav Gobec¹•Institutions (1)

University of Ljubljana¹

01 Aug 2014-Bioorganic Chemistry

TL;DR: This review provides an in-depth insight into the recent developments in the field of inhibitors of the MurA-F enzymes, with special attention given to compounds that act as multiple inhibitors of two, three or more of theMur enzymes.

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69 citations

Journal Article•DOI•

Comparative genomics analysis of Mycobacterium ulcerans for the identification of putative essential genes and therapeutic candidates.

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Azeem Mehmood Butt¹, Izza Nasrullah², Shifa Tahir², Yigang Tong•Institutions (2)

University of the Punjab¹, Quaid-i-Azam University²

13 Aug 2012-PLOS ONE

TL;DR: A computational, comparative genomics workflow was defined for the identification of novel therapeutic candidates against M. ulcerans, with the aim that a selected target should be essential to the pathogen, and have no homology in the human host.

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Abstract: Mycobacterium ulcerans, the causative agent of Buruli ulcer, is the third most common mycobacterial disease after tuberculosis and leprosy. The present treatment options are limited and emergence of treatment resistant isolates represents a serious concern and a need for better therapeutics. Conventional drug discovery methods are time consuming and labor-intensive. Unfortunately, the slow growing nature of M. ulcerans in experimental conditions is also a barrier for drug discovery and development. In contrast, recent advancements in complete genome sequencing, in combination with cheminformatics and computational biology, represent an attractive alternative approach for the identification of therapeutic candidates worthy of experimental research. A computational, comparative genomics workflow was defined for the identification of novel therapeutic candidates against M. ulcerans, with the aim that a selected target should be essential to the pathogen, and have no homology in the human host. Initially, a total of 424 genes were predicted as essential from the M. ulcerans genome, via homology searching of essential genome content from 20 different bacteria. Metabolic pathway analysis showed that the most essential genes are associated with carbohydrate and amino acid metabolism. Among these, 236 proteins were identified as non-host and essential, and could serve as potential drug and vaccine candidates. Several drug target prioritization parameters including druggability were also calculated. Enzymes from several pathways are discussed as potential drug targets, including those from cell wall synthesis, thiamine biosynthesis, protein biosynthesis, and histidine biosynthesis. It is expected that our data will facilitate selection of M. ulcerans proteins for successful entry into drug design pipelines.

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67 citations

Cites background from "Peptidoglycan biosynthesis machiner..."

...The second stage of PG biosynthesis involves transglycosylation and transpeptidation reactions of the disaccharide pentapeptide monomers, and takes place in the periplasmic space catalyzed by several membrane and periplasmic enzymes [61]....
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Journal Article•DOI•

Multitarget ligands in antibacterial research: progress and opportunities.

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Stephen P East, Lynn L. Silver

18 Jan 2013-Expert Opinion on Drug Discovery

TL;DR: This review covers some of the recent progress in identifying new ligands that deliberately interact with more than one essential biological target in bacteria, and the two principal areas covered are inhibitors of DNA replication and cell wall biosynthesis.

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Abstract: Introduction: Resistance to current antibacterial therapies is an inevitability that represents a significant global health concern. Bacteria have the capacity to render all current drug treatments ineffective, which places a demand on the drug discovery community to constantly develop new antibacterial agents. Compounds that inhibit multiple biological targets, often referred to as multitarget ligands, are an inviting prospect in antibacterial research because, although they will not solve the issue of resistance, they might help to delay the onset. Areas covered: This review covers some of the recent progress in identifying new ligands that deliberately interact with more than one essential biological target in bacteria. The two principal areas covered are inhibitors of DNA replication and cell wall biosynthesis. Expert opinion: Antibacterial programs for the design of multitarget ligands present an important opportunity for production of antibacterial agents. Their longevity, due to slow development of...

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56 citations

Cites background from "Peptidoglycan biosynthesis machiner..."

...With the development of robust in vitro assays and highthroughput screening, inhibitors of these enzymes have been identified; however, with the exception of fosfomycin that inhibits MurA, so far there are no other Mur inhibitors that have advanced to the marketplace [50,51]....
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Journal Article•DOI•

Muraymycin nucleoside-peptide antibiotics: uridine-derived natural products as lead structures for the development of novel antibacterial agents.

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Daniel Wiegmann¹, Stefan Koppermann¹, Marius Wirth¹, Giuliana Niro¹, Kristin Leyerer¹, Christian Ducho¹ - Show less +2 more•Institutions (1)

Saarland University¹

22 Apr 2016-Beilstein Journal of Organic Chemistry

TL;DR: This review describes the structures of naturally occurring muraymycins, their mode of action, synthetic access to muray mycins and their analogues, some structure–activity relationship (SAR) studies and first insights into muraysmycin biosynthesis.

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Abstract: Muraymycins are a promising class of antimicrobial natural products. These uridine-derived nucleoside-peptide antibiotics inhibit the bacterial membrane protein translocase I (MraY), a key enzyme in the intracellular part of peptidoglycan biosynthesis. This review describes the structures of naturally occurring muraymycins, their mode of action, synthetic access to muraymycins and their analogues, some structure-activity relationship (SAR) studies and first insights into muraymycin biosynthesis. It therefore provides an overview on the current state of research, as well as an outlook on possible future developments in this field.

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55 citations

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References

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Journal Article•DOI•

Peptidoglycan types of bacterial cell walls and their taxonomic implications.

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Karl-Heinz Schleifer, Otto Kandler

01 Dec 1972-Bacteriological Reviews

3,705 citations

"Peptidoglycan biosynthesis machiner..." refers background in this paper

...The EcMurC enzyme shows a maximum activity at pH 8.6 with K m values of 100 µM, 20 µM and 450 µM for UNAM, L-alanine and ATP/Mg2+, respectively (Liger et al., 1995)....
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...The structures of the substrate and product complexes of HiMurC (Mol et al., 2003) showed that the active site of MurC lies at the junction of the three structural domains and comprises specific binding pockets for the three substrates, UNAM, ATP and L-alanine, distributed around the catalytic centre....
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...For example, all Gram-negative bacteria use meso-DAP in the third position, but a majority of Gram-positive bacteria use L-lysine and a few use other amino acids such as L-ornithine, L-diaminobutyric acid, L-homoserine etc. (Schleifer and Kandler, 1972; Vollmer et al., 2008)....
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...D-glutamic acid is the second amino-acid residue of the peptide stem in most species (Schleifer and Kandler, 1972)....
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...Most Gram-negative bacteria (E. coli) and a few Gram positive bacilli (B. subtilis) contain mesoDAP while most other Gram-positive bacteria (S. aureus and S. pneumoniae) contain L-lysine at the third position of the peptide side chain (Schleifer and Kandler, 1972; Vollmer et al., 2008)....
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Journal Article•DOI•

Antibacterial resistance worldwide: causes, challenges and responses.

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Stuart B. Levy¹, Bonnie Marshall¹•Institutions (1)

Tufts University¹

01 Dec 2004-Nature Medicine

TL;DR: The optimism of the early period of antimicrobial discovery has been tempered by the emergence of bacterial strains with resistance to these therapeutics, and today, clinically important bacteria are characterized not only by single drug resistance but also by multiple antibiotic resistance.

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Abstract: The optimism of the early period of antimicrobial discovery has been tempered by the emergence of bacterial strains with resistance to these therapeutics. Today, clinically important bacteria are characterized not only by single drug resistance but also by multiple antibiotic resistance--the legacy of past decades of antimicrobial use and misuse. Drug resistance presents an ever-increasing global public health threat that involves all major microbial pathogens and antimicrobial drugs.

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3,526 citations

"Peptidoglycan biosynthesis machiner..." refers background in this paper

...The last two decades have seen an unprecedented rise in the emergence of drug resistance in bacterial pathogens (Levy and Marshall, 2004; Levy, 2005; Alekshun and Levy, 2007) especially Mycobacterium tuberculosis, Staphylococcus aureus, Pseudomonas aeruginosa, Enterobacter cloacae, to name a few....
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...The last two decades have seen an unprecedented rise in the emergence of drug resistance in bacterial pathogens (Levy and Marshall, 2004; Levy, 2005; Alekshun and Levy, 2007) especially Mycobacterium tuberculosis, Staphylococcus aureus, Pseudomonas aeruginosa, Enterobacter cloacae, to name a few....
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Journal Article•DOI•

Peptidoglycan structure and architecture

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Waldemar Vollmer¹, Didier Blanot², Miguel A. de Pedro³•Institutions (3)

Newcastle University¹, Centre national de la recherche scientifique², Spanish National Research Council³

01 Mar 2008-Fems Microbiology Reviews

TL;DR: In several species examined, the fine structure of the peptidoglycan significantly varies with the growth conditions, and the different models for the architecture are discussed with respect to structural and physical parameters.

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Abstract: The peptidoglycan (murein) sacculus is a unique and essential structural element in the cell wall of most bacteria. Made of glycan strands cross-linked by short peptides, the sacculus forms a closed, bag-shaped structure surrounding the cytoplasmic membrane. There is a high diversity in the composition and sequence of the peptides in the peptidoglycan from different species. Furthermore, in several species examined, the fine structure of the peptidoglycan significantly varies with the growth conditions. Limited number of biophysical data on the thickness, elasticity and porosity of peptidoglycan are available. The different models for the architecture of peptidoglycan are discussed with respect to structural and physical parameters.

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1,876 citations

"Peptidoglycan biosynthesis machiner..." refers background in this paper

...However, in a few microorganisms such as mycobacteria, 3-3 cross-links between the two meso-DAP residues have been reported (Wietzerbin et al., 1974; Glauner et al., 1988; Vollmer et al., 2008)....
[...]
...For example, all Gram-negative bacteria use meso-DAP in the third position, but a majority of Gram-positive bacteria use L-lysine and a few use other amino acids such as L-ornithine, L-diaminobutyric acid, L-homoserine etc. (Schleifer and Kandler, 1972; Vollmer et al., 2008)....
[...]
...However, in a few microorganisms such as mycobacteria, 3-3 cross-links between the two meso-DAP residues have been reported (Wietzerbin et al., 1974; Glauner et al., 1988; Vollmer et al., 2008)....
[...]
...Cross-linking of the glycan chains generally occurs between the carboxyl group of D-Ala at position 4 and the amino group of meso-DAP at position 3 (4-3 crosslinks), either directly or through a short peptide bridge (Vollmer et al., 2008)....
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...Most Gram-negative bacteria (E. coli) and a few Gram positive bacilli (B. subtilis) contain mesoDAP while most other Gram-positive bacteria (S. aureus and S. pneumoniae) contain L-lysine at the third position of the peptide side chain (Schleifer and Kandler, 1972; Vollmer et al., 2008)....
[...]

Journal Article•DOI•

Molecular Mechanisms of Antibacterial Multidrug Resistance

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Michael N. Alekshun¹, Stuart B. Levy²•Institutions (2)

Schering-Plough¹, Tufts University²

23 Mar 2007-Cell

TL;DR: The intrinsic mechanisms not commonly specified by mobile elements, such as efflux pumps that expel multiple kinds of antibiotics, are now recognized as major contributors to multidrug resistance in bacteria.

...read moreread less

1,446 citations