Bacterial cell walls, inhibitor

Sofia et al. (41) reported a SP library of disaccharides L7 made by 1300 individuals and inspired by the disaccharide core of moenomycin A, a bacterial cell wall inhibitor (Fig. 4.8). Both the structure of the library and its main features are shown in Fig. 4.8. The four major disaccharide scaffolds (X, Y, and W variations) were either built on resin via glycosylation or attached onto the photolabile linker, and subsequently decorated by introduction of Ri, R2, and R3 radiofrequency encoding (42) was used to obtain a large number of discretes with an affordable number of reactions. The... 

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. 

The biochemical basis of penicillin action continues to be an area of active investigation. Penicillins are highly specific inhibitors of enzyme(s) involved in the synthesis of the bacterial cell wall, a structure not present in mammalian cells. Three principal factors are thought to be important for effective antibacterial action by a penicillin ... 

Hen egg-white lysozyme catalyzes the hydrolysis of various oligosaccharides, especially those of bacterial cell walls. The elucidation of the X-ray structure of this enzyme by David Phillips and co-workers (Ref. 1) provided the first glimpse of the structure of an enzyme-active site. The determination of the structure of this enzyme with trisaccharide competitive inhibitors and biochemical studies led to a detailed model for lysozyme and its hexa N-acetyl glucoseamine (hexa-NAG) substrate (Fig. 6.1). These studies identified the C-O bond between the D and E residues of the substrate as the bond which is being specifically cleaved by the enzyme and located the residues Glu 37 and Asp 52 as the major catalytic residues. The initial structural studies led to various proposals of how catalysis might take place. Here we consider these proposals and show how to examine their validity by computer modeling approaches. 

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). 

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 site of action in the 3-lactam antibiotics is muramoylpentapeptide carboxypeptidase, an enzyme that is essential for cross-linking of bacterial cell walls. The antibiotic resembles the substrate of this enzyme (a peptide with the C-terminal sequence D-Ala-D-Ala) and is therefore reversibly bound in the active center. This brings the 3-lactam ring into proximity with an essential serine residue of the enzyme. Nucleophilic substitution then results in the formation of a stable covalent bond between the enzyme and the inhibitor, blocking the active center (see p. 96). In dividing bacteria, the loss of activity of the enzyme leads to the formation of unstable cell walls and eventually death. 

Bacterial cell wall synthesis inhibitor, d-ALANINE-d-ALANINE LIGASE BACTERIAL LEADER PEPTIDASE I Bacterial reorientation,... 

Mechanism of Action Penicillins bind to bacterial cell wall, inhibiting bacterial cell wall synthesis. Therapeutic Effect Inhibits bacterial cell wall synthesis. Beta-lacta-mase inhibitors inhibit the action of bacterial beta-lactamase. Therapeutic Effect Protects the penicillin from enzymatic degradation. 

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

Examples of enzyme inhibitors that can be used as drugs Enzyme inhibitors can be used as drugs, inhibiting either intracellular or extracellular reactions. For example, the p-lactam antibiotics, such as penicillin and amoxicillin, act by inhibiting one or more of the enzymes of bacterial cell wall synthesis. 

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. 

ANTIBIOTICS 0-LACTAMASE INHIBITORS. The antibacterial effectiveness of penicillins, cephalosporins, and other 0-lactam antibiotics depends on selective acylation and consequently, inactivation, of transpeptidases involved in bacterial cell wall synthesis. This acylating ability is a result of the reactivity of the 0-lactam ring (1). Bacteria that are resistant to 0-lactam antibiotics often produce enzymes called 0-lactamases that inactivate the antibiotics by catalyzing the hydrolytic opening of the 0-lactam... 

O-Linked Oligosaccharides Are Responsible for Different Blood Group Types Specific Inhibitors and Mutants Are Used to Explore the Roles of Glycoprotein Carbohydrates Bacterial Cell Wall Synthesis... 

Many therapeutic drugs are enzyme inhibitors. Important examples are penicillin, which inhibits an enzyme necessary for bacterial cell wall syn-... 

As described in the first section of this chapter, D-alanine is an essential constituent of the peptidoglycan layer of bacterial cell wall, but it is not a common metabolite in mammalian cells. Therefore, alanine racemase has been recognized as a suitable target for antibiotics, and a variety of natural and synthetic inhibitors (inactivators) of the enzyme have been reported. 

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