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Category: Bacterial Pathogenesis
Peptidoglycan Synthesis Inhibitors, Page 1 of 2
< Previous page | Next page > /docserver/preview/fulltext/10.1128/9781555815929/9781555812379_Chap12-1.gif /docserver/preview/fulltext/10.1128/9781555815929/9781555812379_Chap12-2.gifAbstract:
Bacterial peptidoglycans were first identified in the 1940s. The nucleotide precursors were isolated and characterized in 1949. Peptidoglycan biosynthesis has been investigated in many bacterial species. The glycan chains of peptidoglycan are small and repeated units composed of N-acetylglucosamine (GlcNAc) and N-acetylmuramic acid (MurNAc). The glmM gene was shown to be essential in Escherichia coli, but genetic data recently suggested that in Staphylococcus aureus there could be an alternative pathway for glucosamine-1-phosphate biosynthesis. The GlmU protein from E. coli is a bifunctional enzyme. Its C-terminal domain catalyzes acetylation of glucosamine-1-phosphate into GlcNAc-1-phosphate, whereas its N-terminal domain catalyzes uridylation to yield UDP-GlcNAc. Nucleoside antibiotics can be subdivided into different classes according to their chemical structures and/or their respective modes of action against MraY: the tunicamycin group, the ribosamino-uridine group, and finally the capuramycin group. Some of them possess activities against gram-positive bacteria, against Mycobacterium spp., and against Pseudomonas spp. This toxicity is explained by their high inhibitory activity upon glycoconjugate biosyntheses, such as of techoic acids, glycosaminoglycans, and glycoproteins. The major component, caprazamycin B, exhibits anti-M. tuberculosis activity and excellent activity against M. avium complex. The major chemical difference observed between liposidomycins and FR-900493 resides in the presence of an N-functionalized amino acid residue in the FR-900493 structure, instead of the diazepanone ring of liposidomycins. Lantibiotics such as mersacidin, are gene-encoded peptides that contain unusual thioether amino acids and/or 3-methyllanthionine.
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UDP-GlcNAc biosynthesis
Lipopolysaccharide (LPS) or UDP-MurNac biosynthesis
Pentapeptide biosynthesis
Mechanism of reaction catalyzed by ATP-dependent amide-forming enzymes (MurC to MurF)
Lipid II biosynthesis
Peptide cross-linking
Transglycosylation
MurA inhibitors
MurB inhibitors
Phosphinate inhibitors of MurC
Phosphinate inhibitors of MurD
Macrocyclic derivatives
Phosphinate inhibitors of MurE
MurF inhibitors ( Gu et al., 2004 )
Classification of MraY inhibitors
MraY enzymatic reaction
Nucleoside antibiotics that are non-MraY inhibitors
Tunicamycins, streptovirudins, and corynetoxins
Ribosaminouridine is the minimal structural requirement in this class to inhibit MraY
Liposidomycin classification
Caprazamycin chemical structure
FR-900493 and compound 77 described in a Fujisawa patent
Muraymycins
Ribosamino-uridine is the template of the riburamycin series
Riburamycins
Uridylpeptide antibiotic template
Mureidomycin, pacidamycin, and napsamycin chemical structures
Dihydropacidamycin D isomers are reduction products of pacidamycin D
Capuramycin template
Amphomycin
HMR 1043 (friulimicin)
MurG enzymatic reaction
Ramoplanin
Mode of action of bacitracin
Moenomycin A
Chlorobiphenyl vancomycin
Riburamycin activity against gram-positive bacteria, including multiresistant strains
Inhibitory activity of capuramycin and closely related compounds against MraY
Evaluation of capuramycin and related compounds against MraY and M. smegmatis
Evaluation of capuramycin and related compounds against M. avium, M. intracellulare, and M. kansasii and comparison with rifampin and isoniazid
In vitro activity of HMR 1043