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British Poultry Science Jun 20241. The objective of this study was to investigate the protective effects of a peptidoglycan produced by against aflatoxin B (AFB) induced toxicity and in broiler...
peptidoglycan alleviates aflatoxin B-induced toxicity through adsorbing toxins and improving growth, antioxidant status, immunity and liver pathological changes in chicks.
1. The objective of this study was to investigate the protective effects of a peptidoglycan produced by against aflatoxin B (AFB) induced toxicity and in broiler chicks.2. Toxin adsorption experiments were carried out firstly . These experiments indicated that the absorption efficiency of the peptidoglycan for AFB was 64.3-75.9%.3. In the experiments, Hy-Line Brown chicks were fed a diet containing AFB at 71.43 µg/kg with and without peptidoglycan supplementation at concentrations of 100, 200, or 300 g/kg feed from 0-42 d of age.4. The peptidoglycan supplementation in AFB-contaminated diets resulted in significant improvements in terms of average daily gain, feed intake, feed conversion ratio, white blood cell count, haemoglobin content, glutathione peroxidase activity, immunoglobulin (Ig) A, IgG, IgM and Newcastle disease virus antibody titres ( < 0.05) and diminished liver steatosis.5. In conclusion, peptidoglycan supplementation alleviated AFB-induced toxicity through adsorbing toxins and improving growth performance, antioxidant ability, immunity and liver pathological changes in chicks. The optimal supplemental dose was 200 mg/kg in feed.
Topics: Animals; Chickens; Aflatoxin B1; Animal Feed; Peptidoglycan; Limosilactobacillus reuteri; Diet; Poultry Diseases; Antioxidants; Dietary Supplements; Liver; Male; Random Allocation; Dose-Response Relationship, Drug
PubMed: 38466183
DOI: 10.1080/00071668.2024.2316228 -
ACS Infectious Diseases Feb 2024The unique structural architecture of the peptidoglycan allows for the stratification of bacteria as either Gram-negative or Gram-positive, which makes bacterial cells... (Review)
Review
The unique structural architecture of the peptidoglycan allows for the stratification of bacteria as either Gram-negative or Gram-positive, which makes bacterial cells distinguishable from mammalian cells. This classification has received attention as a potential target for diagnostic and therapeutic purposes. Bacteria's ability to metabolically integrate peptidoglycan precursors during cell wall biosynthesis and recycling offers an opportunity to target and image pathogens in their biological state. This Review explores the peptidoglycan biosynthesis for bacteria-specific targeting for infection imaging. Current and potential radiolabeled peptidoglycan precursors for bacterial infection imaging, their development status, and their performance and/or are highlighted. We conclude by providing our thoughts on how to shape this area of research for future clinical translation.
Topics: Animals; Bacteria; Bacterial Infections; Cell Wall; Mammals; Peptidoglycan
PubMed: 38290525
DOI: 10.1021/acsinfecdis.3c00443 -
ACS Infectious Diseases Jul 2023Traditional antibacterial screens rely on growing bacteria in nutrient-replete conditions which are not representative of the natural environment or sites of infection....
Traditional antibacterial screens rely on growing bacteria in nutrient-replete conditions which are not representative of the natural environment or sites of infection. Instead, screening in more physiologically relevant conditions may reveal novel activity for existing antibiotics. Here, we screened a panel of antibiotics reported to lack activity against the opportunistic Gram-negative bacterium, , under low-nutrient and low-iron conditions, and discovered that the glycopeptide vancomycin inhibited the growth of at low micromolar concentrations through its canonical mechanism of action, disruption of peptidoglycan crosslinking. Spontaneous vancomycin-resistant mutants underwent activating mutations in the sensor kinase of the two-component CpxSR system, which induced cross-resistance to almost all classes of β-lactams, including the siderophore antibiotic cefiderocol. Other mutations that conferred vancomycin resistance mapped to WapR, an α-1,3-rhamnosyltransferase involved in lipopolysaccharide core biosynthesis. A WapR P164T mutant had a modified LPS profile compared to wild type that was accompanied by increased susceptibility to select bacteriophages. We conclude that screening in nutrient-limited conditions can reveal novel activity for existing antibiotics and lead to discovery of new and impactful resistance mechanisms.
Topics: Vancomycin; Pseudomonas aeruginosa; Anti-Bacterial Agents; Glycopeptides; Nutrients
PubMed: 37279282
DOI: 10.1021/acsinfecdis.3c00167 -
Environmental Research Jul 2023Ruminant animals house a dense and diverse community of microorganisms in their rumen, an enlarged compartment in their stomach, which provides a supportive environment... (Review)
Review
Ruminant animals house a dense and diverse community of microorganisms in their rumen, an enlarged compartment in their stomach, which provides a supportive environment for the storage and microbial fermentation of ingested feeds dominated by plant materials. The rumen microbiota has acquired diverse and functionally overlapped enzymes for the degradation of plant cell wall polysaccharides. In rumen Bacteroidetes, enzymes involved in degradation are clustered into polysaccharide utilization loci to facilitate coordinated expression when target polysaccharides are available. Firmicutes use free enzymes and cellulosomes to degrade the polysaccharides. Fibrobacters either aggregate lignocellulose-degrading enzymes on their cell surface or release them into the extracellular medium in membrane vesicles, a mechanism that has proven extremely effective in the breakdown of recalcitrant cellulose. Based on current metagenomic analyses, rumen Bacteroidetes and Firmicutes are categorized as generalist microbes that can degrade a wide range of polysaccharides, while other members adapted toward specific polysaccharides. Particularly, there is ample evidence that Verrucomicrobia and Spirochaetes have evolved enzyme systems for the breakdown of complex polysaccharides such as xyloglucans, peptidoglycans, and pectin. It is concluded that diversity in degradation mechanisms is required to ensure that every component in feeds is efficiently degraded, which is key to harvesting maximum energy by host animals.
Topics: Animals; Metagenome; Rumen; Lignin; Bacteria; Polysaccharides; Bacteroidetes
PubMed: 37086884
DOI: 10.1016/j.envres.2023.115925 -
RSC Medicinal Chemistry Nov 2023Antimicrobial resistance (AMR) in bacterial pathogens is a worldwide health issue. The innovation gap in discovering new antibiotics has remained a significant hurdle in... (Review)
Review
Antimicrobial resistance (AMR) in bacterial pathogens is a worldwide health issue. The innovation gap in discovering new antibiotics has remained a significant hurdle in combating the AMR problem. Currently, antibiotics target various vital components of the bacterial cell envelope, nucleic acid and protein biosynthesis machinery and metabolic pathways essential for bacterial survival. The critical role of the bacterial cell envelope in cell morphogenesis and integrity makes it an attractive drug target. While a significant number of in-clinic antibiotics target peptidoglycan biosynthesis, several components of the bacterial cell envelope have been overlooked. This review focuses on various antibacterial targets in the bacterial cell wall and the strategies employed to find their novel inhibitors. This review will further elaborate on combining forward and reverse chemical genetic approaches to discover antibacterials that target the bacterial cell envelope.
PubMed: 37974958
DOI: 10.1039/d3md00143a -
ACS Omega Feb 2024The absolute configuration dictates the biological role of chiral molecules in the living world. This is best exemplified by all ribosomally synthesized polypeptides... (Review)
Review
The absolute configuration dictates the biological role of chiral molecules in the living world. This is best exemplified by all ribosomally synthesized polypeptides having chiral amino acids only in the l-configuration. However, d-amino acids are also associated with various vital biological processes such as peptidoglycan of the bacterial cell wall, ligands for neurotransmitters, molecules involved in signaling, and precursors of metabolites, to name a few. The occurrence of both l- and d-enantiomers of amino acids in the living systems necessitates the presence of enzymes that exhibit stereoselectivity in recognition of substrates. This mini-review summarizes the overall mechanistic insights into the interconversion of l- and d-amino acids by the amino acid racemases. We discuss the structural, mechanistic, and evolutionary relationship of four crucial enzymes that catalyze the oxidative deamination of l- or d-amino acids and their physiological role in microbes and higher organisms. We highlight the physiological implications of d-amino acid oxidase and d-aspartate oxidase in human health and diseases and their applications as drug targets. Finally, we summarize the potential applications of microbially obtained chiral-selective enzymes as biocatalysts and for various industrial purposes.
PubMed: 38343938
DOI: 10.1021/acsomega.3c08305 -
Antibiotics (Basel, Switzerland) Jan 2024β-Lactams are the most widely prescribed class of antibiotics that inhibit penicillin-binding proteins (PBPs), particularly transpeptidases that function in... (Review)
Review
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.
PubMed: 38247618
DOI: 10.3390/antibiotics13010059 -
Protein Science : a Publication of the... Nov 2023Bacterial WxL proteins contain peptidoglycan-binding WxL domains, which have a dual Trp-x-Leu motif and are involved in virulence. It was recently shown that WxL...
Bacterial WxL proteins contain peptidoglycan-binding WxL domains, which have a dual Trp-x-Leu motif and are involved in virulence. It was recently shown that WxL proteins occur in gene clusters, containing typically a small WxL protein (which in the mature protein consists only of a WxL domain), a large WxL protein (which contains a C-terminal WxL domain with N-terminal host-binding domains), and a conserved protein annotated as a Domain of Unknown Function (DUF). Here we analyze this DUF and show that it contains two tandem domains-DUF916 and DUF3324-which both have an IgG-like fold and together form a single functional unit, connected to a C-terminal transmembrane helix. DUF3324 is a stable domain, while DUF916 is less stable and is likely to require a stabilizing interaction with WxL. The protein is suggested to have an important role to bind and stabilize WxL on the peptidoglycan surface, via the DUF916 domain, and to bind to host cells via the DUF3324 domain. AlphaFold2 predicts that a β-hairpin strand from DUF916 inserts into WxL adjacent to its N-terminus. We therefore propose to rename the DUF916-DUF3324 pair as WxL Interacting Protein (WxLIP), with DUF916, DUF3324 and the transmembrane helix forming the first, second and third domains of WxLIP, which we characterize as peptidoglycan binding domain (PGBD), host binding domain (HBD), and transmembrane helix (TMH) respectively.
Topics: Peptidoglycan; Bacterial Proteins; Protein Binding; Virulence
PubMed: 37833244
DOI: 10.1002/pro.4806 -
European Journal of Pharmaceutical... Dec 2023Staphylococcus aureus is an important pathogenic bacterium responsible for various organ infections. The serious side effects and the development of antibiotic...
Staphylococcus aureus is an important pathogenic bacterium responsible for various organ infections. The serious side effects and the development of antibiotic resistance have rendered the antibiotic therapy against S. aureus increasingly challenging, emphasizing the pressing need for the exploration of novel therapeutic agents. Our research has uncovered the promising antimicrobial properties of 8-octyl berberine (OBBR), a novel compound derived from berberine (BBR), against S. aureus. OBBR exhibited a minimum inhibitory concentration (MIC) of 1.0 μg/mL, which closely approximated that of levofloxacin. Intriguingly, a multipassage resistance assay demonstrated that the MIC of OBBR against S. aureus remained relatively stable, while levofloxacin exhibited a 4-fold increase over 20 days, suggesting that OBBR was less prone to inducing resistance. Mechanistically, our investigation, employing Zeta potential measurements, flow cytometry, scanning electron microscopy, and transmission electron microscopy, unveiled that OBBR induced morphological alterations in the bacteria. Furthermore, it disrupted the bacterial cell wall and membrane by altering membrane potential and compromising membrane integrity. These actions culminated in bacterial disintegration and apoptosis. Transcriptomic analysis shed light on significant downregulation of gene ontology terms, predominantly associated with membranes. The Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis implicated OBBR in disturbing peptidoglycan biosynthesis, with the membrane protein MraY emerging as a potential target for OBBR's action against S. aureus. Notably, experiments involving the overexpression of MraY confirmed OBBR's inhibitory effect on peptidoglycan synthesis. Furthermore, molecular docking and cellular thermal shift assay revealed OBBR's direct interaction with MraY, potentially leading to the inhibition of the enzymatic activity of MraY and, consequently, impeding peptidoglycan synthesis. In summary, OBBR, by targeting MraY and inhibiting peptidoglycan synthesis, emerges as a promising alternative antibiotic against S. aureus, offering potential advantages in terms of limited drug resistance development.
Topics: Humans; Staphylococcus aureus; Berberine; Peptidoglycan; Molecular Docking Simulation; Levofloxacin; Anti-Bacterial Agents; Staphylococcal Infections; Microbial Sensitivity Tests
PubMed: 37806408
DOI: 10.1016/j.ejps.2023.106602 -
Current Opinion in Microbiology Jun 2024The governing principles and suites of genes for lateral elongation or incorporation of new cell wall material along the length of a rod-shaped cell are well described.... (Review)
Review
The governing principles and suites of genes for lateral elongation or incorporation of new cell wall material along the length of a rod-shaped cell are well described. In contrast, relatively little is known about unipolar elongation or incorporation of peptidoglycan at one end of the rod. Recent work in three related model systems of unipolar growth (Agrobacterium tumefaciens, Brucella abortus, and Sinorhizobium meliloti) has clearly established that unipolar growth in the Hyphomicrobiales order relies on a set of genes distinct from the canonical elongasome. Polar incorporation of envelope components relies on homologous proteins shared by the Hyphomicrobiales, reviewed here. Ongoing and future work will reveal how unipolar growth is integrated into the alphaproteobacterial cell cycle and coordinated with other processes such as chromosome segregation and cell division.
Topics: Brucella abortus; Sinorhizobium meliloti; Bacterial Proteins; Agrobacterium tumefaciens; Cell Wall; Peptidoglycan; Cell Division
PubMed: 38569420
DOI: 10.1016/j.mib.2024.102470