Cell wall biosynthesis inhibitors

Further support for cell wall biosynthesis as a target site was provided by Umetsu et al, who reported abnormal swelling of cultured soybean cells treated with dichlobenil. Dichlobenil was also shown to be an effective and reversible inhibitor of cell wall formation in tobacco protoplasts. It was considerably more potent than other cell wall inhibitors, such as coumarin, and it caused the formation of multinucleate protoplasts. Inhibition of cellulose biosynthesis prevented cell wall formation and cytokinesis but nuclear division that is, mitosis was unaffected. Further studies with tobacco protoplasts confirmed the specific and potent inhibition associated with the cellulose-synthesizing complex at the plasma membrane. 

P-lactam antibiotics, exert thek antibacterial effect by interfering with the synthesis of the bacterial cell wall. These antibiotics tend to be "kreversible" inhibitors of cell wall biosynthesis and they are usually bactericidal at concentrations close to thek bacteriostatic levels. Cephalospotins are widely used for treating bacterial infections. They are highly effective antibiotics and have low toxicity. 

Tipper D.J. (1988) Antibiotic Inhibitors cf Bacterial Cell Wall Biosynthesis, 2nd edn. Oxford Pergamon Press. 

Examples of successful natural product screens directed against proven targets include screens designed to look for inhibitors of bacterial cell wall biosynthesis. These screens were established once it became clear... 

For each structural class of antibacterial discussed, there are many members in chnical use. I have selected a few as representative examples of each class. There are several additional classes of antibacterials as well. Notable is vancomycin (Vancocin), like the p-lactam antibacterials an inhibitor of cell wall biosynthesis although the site... 

As a result, the penicillin occupies the active site of the enzyme, and becomes bound via the active-site serine residue. This binding causes irreversible enzyme inhibition, and stops cell-wall biosynthesis. Growing cells are killed due to rupture of the cell membrane and loss of cellular contents. The binding reaction between penicillinbinding proteins and penicillins is chemically analogous to the action of P-lactamases (see Boxes 7.20 and 13.5) however, in the latter case, penicilloic acid is subsequently released from the P-lactamase, and the enzyme can continue to function. Inhibitors of acetylcholinesterase (see Box 7.26) also bind irreversibly to the enzyme through a serine hydroxyl. 

Fluoro amino acids have been incorporated into peptides, in order to ease the transport or reduce the systemic toxicity. Thus, trifluoroalanine, a powerful inhibitor of alanine racemase, is an essential enzyme for the biosynthesis of the cell wall of bacteria. It has a low antibiotic activity because of its very poor transport. In order to facilitate this transport, the amino acid has been incorporated into a peptide. This delivery allows a reduction of the doses, and thus the toxicity of the treatment is lowered.3-FIuorophenylaIanine (3-F-Phe) is a substrate of phenylalanine hydroxylase, which transforms it into 3-F-Tyr. 3-F-Tyr has a high toxicity for animals, due to its ultimate metabolization into fluorocitrate, a powerful inhibitor of the Krebs cycle (cf. Chapter 7). 3-F-Phe has a low toxicicity toward fungus cells, but when delivered as a tripeptide 3-F-Phe becomes an efficient inhibitor of the growth of Candida albicans. This tripeptide goes into the cell by means of the active transport system of peptides, where the peptidases set free the 3-F-Phe. ... 

The thiopyrano[4,3-c]pyrazole 206 has been found to be a good inhibitor of bacterial cell wall biosynthesis <2003BML2591>. 

Polyoxins are inhibitors of chitin biosynthesis. Chitin is a component of fungal cell walls except in Phycomycete fungi these contain cellulose as their major cell wall constituent, hence polyoxins are inactive against Plasmopara, Pythium and Phytophthora. 

Another enzyme-activated inhibitor is the streptomyces antibiotic D-cycloserine (oxamycin), an antitubercular drug that resembles D-alanine in structure. A potent inhibitor of alanine racemase, it also inhibits die non-PLP, ATP-dependent, D-alanyl-D-alanine synthetase which is needed in the biosynthesis of die peptidoglycan of bacterial cell walls. 

Another group of fungicides interferes with cell wall formation. Two examples of this group include 1) the polyoxines, which prevent chitin formation by competitively inhibiting chitin-synthase, the final enzyme involved in chitin biosynthesis, and 2) melanine biosynthesis inhibitors, especially in Pyricularia oryzae. Examples of... 

Cell wall biosynthesis is a target of many commonly used antibiotics. The unique nature of the cell wall allows specific inhibitors of this process to be... 

UDP-A-MurNAc-depsipentapeptide) derivatives including fluorescent-labeled derivatives. Shin-ichiro Nishimura et al. reported the synthesis of UDP-MurNAc-pentapeptide derivatives possessing a levulinyl (Lev) group on the side chain of the Lys residue [82, 83] for subsequent introduction of fluorescent label or oligosaccharide moieties by oxime formation after their incorporation through cell-wall biosynthesis. The 4-fluorinated UDP-MurNAc-pentapeptide was also synthesized as a stable biosynthesis inhibitor [84],... 

Aiming at the discovery of novel inhibitors of cell wall arabinan portion biosynthesis, Lowary and Callam [10] designed an elegant route to methyl carbafuranosides 43 and 44, employing, as the key step, a ring closing metathesis reaction. 

FIGURE 3.9 Libraries tested as inhibitors of enzymes involved in the biosynthesis of the mycobacterium cell wall. 

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