Bacterial cell wall biosynthesis, inhibitors

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... 

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

FIGURE 9.26 Inhibitors of bacterial cell wall biosynthesis. 

Inhibitors of Bacterial Cell Wall Biosynthesis. Interestingly, iminoalditol 81 (Figure 9.26) was found active against the Mycobacterium avium complex in an infected macrophage model at 4 p.g/ml [212]. Furthermore, this compound increased tumor necrosis factor a (TNFa) production in the infected cells. 

Inhibitors of the bacterial cell wall biosynthesis enzyme MurD. Bioorg. Med. Chem. Lett., 8, 1643-1648. 

Earlier, Kutterer et al. (05BMCL2527) (Scheme 80) reported that 4-methyl-1,2-fazs(4-chlorophenyl)pyrazolidine-3,5-dione 348 with 2-bromo-l-(2,4-difluoro-phenyl)ethanone 349 in toluene containing DIPEA under MW heating (900 W) for 1 min gave 4 -alkyl-4-methyl-pyrazolidine-3,5-dione 350 and 4-methyl-5-alkyloxy-pyrazol-3-one 351. Although compound 351 was evaluated as new inhibitor of bacterial cell wall biosynthesis, no separation and yields of 350 and 351 were reported. 

In conjunction with our overview of glycomimetics that block protein-carbohydrate interactions, we also discuss strategies to develop inhibitors of carbohydrate-processing enzymes this section focuses on the enzymes involved in bacterial cell wall biosynthesis because it is an area in which many new advances have been made. Enzymes that utilize sugars and synthesize glycoconjugates unique to pathogens have been identified, and cell-permeable inhibitors can be used to explore their biological roles or validate a potential... 

Ribosylation of isopropylideneuridine and subsequent manipulations led to the synthesis of 170 (R = H), which constitutes a part-structure of the liposidomycin class of antibiotics. The two isomers of 170 (R = CH2OH) were also prepared in synthetic sequences that involved ribosylation of D-allofuranose and L-talofuranose derivatives at 0-5, with introduction of uracil at a late stage. Molecular modelling was carried out of both liposidomycins and tunicamycin with the UDP-iV-acetylmuramic acid-pentapeptide that is the substrate for the enzyme (translocase) in bacterial cell wall biosynthesis that the antibiotics inhibit, and, in accordance with the predictions, only the 5-isomer of 170 (R = CH2OH) was a good inhibitor. ... 

Ward, J. B. In Antibiotic Inhibitors of Bacterial Cell Wall Biosynthesis Tipper, D. J. Ed Pergamon Press 1987, p.1-43. 

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. 

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. 

Experimental evidence also supported the hypothesis that the disaccharide analogs inhibit bacterial growth by inhibiting cell wall biosynthesis. They demonstrated bactericidal activity only in actively growing cells, and cells pretreated with protein synthesis inhibitors were resistant to the effects of the disaccharide analogs. In addition, they inhibited incorporation of lysine into cell wall material in intact Ent. faecalis. ... 

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