Peptidoglycans synthesis

Vancomycin is bactericidal to most susceptible bacteria at concentrations near its minimum inhibitory concentration (MIC) and is an inhibitor of bacterial cell wall peptidoglycan synthesis, although at a site different from that of j3-lactam antibiotics (Chapter 9). 

Bacterial cell wall j3-Lactams Glyoopeptides Cycloserine Isoniazid Ethambutol Inhibit peptidoglycan synthesis Inhibit peptidoglycan synthesis Inhibits peptidoglycan synthesis Inhibits mycolic acid synthesis Inhibits arabinogalactan synthesis None in mammalian cells None in mammalian cells None in mammalian cells None in mammalian cells None in mammalian cells... 

Intrinsic and acquired resistance 3.3 Inhibitors of peptidoglycan synthesis... 

Fosfomycin inhibits pyruvil transferase, which is an enzyme involved in peptidoglycan synthesis. Two mechanisms of acquired resistance have been described for fosfomycin (Davies 1994). 

Mode of action Interferes with bacterial cell wall synthesis during active multiplication, causing cell wall death and resultant bactericidal activity Inhibits bacterial cell wall synthesis by binding to one or more of the penicillin-binding proteins, which in turn inhibit the final transpeptidation step of peptidoglycan synthesis in bacterial cell walls bacteria usually lyse from ongoing autolytic enzyme activity... 

Aretz W, Meiwes J, Seibert Q Vobis Ci Wink J. (2000) Frinlimicins novel lipopeptide antibiotics with peptidoglycan synthesis inhibiting activity from Actinoplanes Friuliensis sp nov. J Antibiot 53 807-815. 

This enzyme catalyzes the transamination of a wide spectrum of a-amino acids and a-keto (or 2-oxo) acids, demonstrating absolute specificity for their D-isomers. The most likely physiologic role is to provide D-amino acids for peptidoglycan synthesis in bacterial cell wall formation. 

Mode of Action. Penicillins exeit their antibacterial effect by inhibiting the high molecular weight penicillin-binding proteins (PBPs) that are implicated in the final stages of peptidoglycan synthesis. 

The next stage in peptidoglycan synthesis results from poly- merization of A-acetylglucosamine and N-acetyl muramyl-pentapeptide containing residues into peptidoglycan [ strands. The relevant reactions take place on the inner sur-i face of the plasma membrane (fig. 16.17). f In step 1 (see fig. 16.17), UDP-N-acetyl muramyl-... 

Most biologically active natural peptides are linear, but bacitracin is a leading member of the so-called cyclic peptide type of antibiotics. The commercial material, extracted from Bacillus subtilis, is a mixture of several compounds in which bacitracin A predominates. It exerts its action by inhibiting peptidoglycan synthesis and membrane function. Bacitracin has been a useful antibiotic since the 1960s, but its systemic use results in a number of toxic side effects, including nephrotoxicity. One cannot be sure which components of the mixture are responsible for the toxicity, and separation of natural constituents is complex and difficult. For this reason, an efficient synthesis of bacitracin A would be useful. 

McPherson DC, Popham DL. Peptidoglycan synthesis in the absence of class A penicillin-binding proteins in Bacillus subtilis. J Bacteriol. 2003 185 1423-1431. 

F Ishino, K Mitsui, S Tamaki, M Matsuhashi. Dual enzyme activities of cell wall peptidoglycan synthesis peptidoglycan transglycosylase and penicillin-sensitive transpeptidase in purified preparations of Escherichia coli penicillin-binding protein la. Biochem Biophys Res Commun 97 287-293, 1980. 

M Matsuhashi. Utilization of lipid-linked precursors and the formation of peptidoglycan in the process of cell growth and division membrane enzymes involved in the final steps of peptidoglycan synthesis and the mechanism of their regulation. In JM Ghuysen, R Hakenbeck, eds. Bacterial Cell Wall. Amsterdam, The Netherlands Elsevier Science, 1994, pp 55-72. 

S Tamaki, S Nakajima, M Matsuhashi. Thermosensitive mutation in Escherichia coli simultaneously causing defects in penicillin-binding protein-lb and in enzyme activity for peptidoglycan synthesis in vitro. Proc Natl Acad Sci (USA) 74 5472-5476, 1977. 

D Mengin-Lecreulx, B Flouret, J van Heijenoort. Cytoplasmic steps of peptidoglycan synthesis in Escherichia coli. J Bacteriol 151 1109-1117, 1982. 

WS Faraci. Cytosolic enzymes in peptidoglycan synthesis as potential antibacterial targets. In J Sutcliffe, NH Georgopapadakou, eds. Emerging Targets in Antibacterial and Antifungal Chemotherapy. New York Chapman Hall, 1992, pp 176-204. 

SA Denome, PK Elf, TA Henderson, DE Nelson, KD Young. Escherichia coli mutants lacking all possible combinations of eight penicillin binding proteins viability, characteristics, and implications for peptidoglycan synthesis. J Bacteriol 181 ... 

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