Peptidoglycan or murein is a unique large macromolecule, a polysaccharide, consisting of sugars and amino acids that forms a mesh-like layer (sacculus) that surrounds the bacterial cytoplasmic membrane. The sugar component consists of alternating residues of β-(1,4) linked N-acetylglucosamine (NAG) and N-acetylmuramic acid (NAM). Attached to the N-acetylmuramic acid is an oligopeptide chain made of three to five amino acids. The peptide chain can be cross-linked to the peptide chain of another strand forming the 3D mesh-like layer. Peptidoglycan serves a structural role in the bacterial cell wall, giving structural strength, as well as counteracting the osmotic pressure of the cytoplasm. This repetitive linking results in a dense peptidoglycan layer which is critical for maintaining cell form and withstanding high osmotic pressures, and it is regularly replaced by peptidoglycan production. Peptidoglycan hydrolysis and synthesis are two processes that must occur in order for cells to grow and multiply, a technique carried out in three stages: clipping of current material, insertion of new material, and re-crosslinking of existing material to new material.
Teicoplanin is an semisynthetic glycopeptide antibiotic with a spectrum of activity similar to vancomycin. Its mechanism of action is to inhibit bacterial cell wall peptidoglycan synthesis. It is used in the prophylaxis and treatment of serious infections caused by Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus and Enterococcus faecalis.
Heparan sulfate (HS) is a linear polysaccharide found in all animal tissues. It occurs as a proteoglycan in which two or three HS chains are attached in close proximity to cell surface or extracellular matrix proteins. In this form, HS binds to a variety of protein ligands, including Wnt, and regulates a wide range of biological activities, including developmental processes, angiogenesis, blood coagulation, abolishing detachment activity by GrB, and tumour metastasis. HS has also been shown to serve as cellular receptor for a number of viruses, including the respiratory syncytial virus. One study suggests that cellular heparan sulfate has a role in SARS-CoV-2 Infection, particularly when the virus attaches with ACE2.
Tunicamycin is a mixture of homologous nucleoside antibiotics that inhibits the UDP-HexNAc: polyprenol-P HexNAc-1-P family of enzymes. In eukaryotes, this includes the enzyme GlcNAc phosphotransferase (GPT), which catalyzes the transfer of N-acetylglucosamine-1-phosphate from UDP-N-acetylglucosamine to dolichol phosphate in the first step of glycoprotein synthesis. Tunicamycin blocks N-linked glycosylation (N-glycans) and treatment of cultured human cells with tunicamycin causes cell cycle arrest in G1 phase. It is used as an experimental tool in biology, e.g. to induce unfolded protein response. Tunicamycin is produced by several bacteria, including Streptomyces clavuligerus and Streptomyces lysosuperificus.
Uridine diphosphate N-acetylglucosamine or UDP-GlcNAc is a nucleotide sugar and a coenzyme in metabolism. It is used by glycosyltransferases to transfer N-acetylglucosamine residues to substrates. D-Glucosamine is made naturally in the form of glucosamine-6-phosphate, and is the biochemical precursor of all nitrogen-containing sugars. To be specific, glucosamine-6-phosphate is synthesized from fructose 6-phosphate and glutamine as the first step of the hexosamine biosynthesis pathway. The end-product of this pathway is UDP-GlcNAc, which is then used for making glycosaminoglycans, proteoglycans, and glycolipids.
In enzymology, N-acetylglucosamine-6-phosphate deacetylase (EC 3.5.1.25), also known as GlcNAc-6-phosphate deacetylase or NagA, is an enzyme that catalyzes the deacetylation of N-acetylglucosamine-6-phosphate (GlcNAc-6-P) to glucosamine-6-phosphate (GlcN-6-P):
In enzymology, an acyl-[acyl-carrier-protein]-UDP-N-acetylglucosamine O-acyltransferase is an enzyme that catalyzes the chemical reaction
In enzymology, an UDP-N-acetylglucosamine 1-carboxyvinyltransferase is an enzyme that catalyzes the first committed step in peptidoglycan biosynthesis of bacteria:
UDP-N-acetylglucosamine—dolichyl-phosphate N-acetylglucosaminephosphotransferase is an enzyme that in humans is encoded by the DPAGT1 gene.
Ribostamycin is an aminoglycoside-aminocyclitol antibiotic isolated from a streptomycete, Streptomyces ribosidificus, originally identified in a soil sample from Tsu City of Mie Prefecture in Japan. It is made up of 3 ring subunits: 2-deoxystreptamine (DOS), neosamine C, and ribose. Ribostamycin, along with other aminoglycosides with the DOS subunit, is an important broad-spectrum antibiotic with important use against human immunodeficiency virus and is considered a critically important antimicrobial by the World Health Organization., Resistance against aminoglycoside antibiotics, such as ribostamycin, is a growing concern. The resistant bacteria contain enzymes that modify the structure through phosphorylation, adenylation, and acetylation and prevent the antibiotic from being able to interact with the bacterial ribosomal RNAs.
Bacillithiol is a thiol compound found in Bacillus species. It is likely involved in maintaining cellular redox balance and plays a role in microbial resistance to the antibiotic fosfomycin.
In molecular biology, UDP-3-O-N-acetylglucosamine deacetylase, EC 3.5.1.-, is a bacterial enzyme involved in lipid A biosynthesis.
UDP-3-O-(3-hydroxymyristoyl)glucosamine N-acyltransferase is an enzyme with systematic name (3R)-3-hydroxymyristoyl-(acyl-carrier protein):UDP-3-O-( -3-hydroxymyristoyl)-alpha-D-glucosamine N-acetyltransferase. This enzyme catalyses the following chemical reaction
Protein O-GlcNAc transferase also known as OGT or O-linked N-acetylglucosaminyltransferase is an enzyme that in humans is encoded by the OGT gene. OGT catalyzes the addition of the O-GlcNAc post-translational modification to proteins.
UDP-GlcNAc:ribostamycin N-acetylglucosaminyltransferase is an enzyme with systematic name UDP-N-acetyl-alpha-D-glucosamine:ribostamycin N-acetylglucosaminyltransferase. This enzyme catalyses the following chemical reaction
The alpha-D-phosphohexomutases are a large superfamily of enzymes, with members in all three domains of life. Enzymes from this superfamily are ubiquitous in organisms from E. coli to humans, and catalyze a phosphoryl transfer reaction on a phosphosugar substrate. Four well studied subgroups in the superfamily are:
- Phosphoglucomutase (PGM)
- Phosphoglucomutase/Phosphomannomutase (PGM/PMM)
- Phosphoglucosamine mutase (PNGM)
- Phosphoaceytlglucosamine mutase (PAGM)
UDP-N-acetylglucosamine—undecaprenyl-phosphate N-acetylglucosaminephosphotransferase is an enzyme with systematic name UDP-N-acetyl-alpha-D-glucosamine:ditrans,octacis-undecaprenyl phosphate N-acetyl-alpha-D-glucosaminephosphotransferase. This enzyme catalyses the following chemical reaction
UDP-2,3-diacylglucosamine diphosphatase (EC 3.6.1.54, UDP-2,3-diacylglucosamine hydrolase, UDP-2,3-diacylglucosamine pyrophosphatase, ybbF (gene), lpxH (gene)) is an enzyme with systematic name UDP-2,3-bis((3R)-3-hydroxymyristoyl)-alpha-D-glucosamine 2,3-bis((3R)-3-hydroxymyristoyl)-beta-D-glucosaminyl 1-phosphate phosphohydrolase. This enzyme catalyses the following chemical reaction
LPC-233 is an experimental antibiotic drug. It acts as a potent and selective inhibitor of the bacterial enzyme UDP-3-O-acyl-N-acetylglucosamine deacetylase (LpxC), which is important for the production of Lipid A, a key component of the cell membrane of Gram-negative bacteria. Various inhibitors of LpxC have been developed but none have yet progressed into clinical trials in humans, mostly because of off-target cardiovascular toxicity. LPC-233 is one of the most advanced drugs of this type in preclinical testing, showing activity against several pathogens of concern such as multidrug-resistant Pseudomonas aeruginosa and carbapenem resistant Enterobacter strains, and with no cardiovascular toxicity evident in testing on mice and dogs.
TP0586532 is an experimental antibiotic drug, which acts as a potent and selective inhibitor of the bacterial enzyme UDP-3-O-acyl-N-acetylglucosamine deacetylase (LpxC). This enzyme is important for the production of Lipid A, a key component of the cell membrane of Gram-negative bacteria. Previous inhibitors of LpxC have failed to progress into clinical trials in humans, mostly because of off-target cardiovascular toxicity, so TP0586532 was based on a different structural class which is hoped to reduce this risk. In animal studies it shows activity against carbapenem-resistant Klebsiella pneumoniae but has not yet progressed into human trials.
