Antibiotics D-cycloserine

Fig. 8.1 Biosynthesis of peptidoglycan. The large circles represent A -acetylglucosamine orN-acetylmuramic acid to the latter is linked initially a pentapeptide chain comprising L-alanine, D-glutamic acid and meso-diaminopiraelic acid (small circles) terminating in two D-alanine residues (small, darker circles). The lipid molecule is undecaprenyl phosphate. In the initial (cytoplasm) stage where inhibition by the antibiotic D-cycloserine is shown, two molecules of Dalanine (small circles) are converted by an isomerase to the D-forms (small, darker circles), alter which a ligase joins the two D-alanines together to produce a D-alanyl-D-alanine dipeptide.

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. 

Reitz, R., Slade, H., Neuhaus, F. (1967). The biochemical mechanisms of resistance by Streptococci to the antibiotics D-cycloserine and O-carbamyl-D-serine. Biochemistry, 6, 2561-2570. 

The antibiotics D-cycloserine and 0-carbamyl D-serine are irreversible inhibitors of certain pyridoxal phosphate containing enzymes27,28,29 ... 

D-Cycloserine (Figure 7.17) is produced by cultures of Streptomyces orchidaceus, or may be prepared synthetically, and is probably the simplest substance with useful antibiotic... 

D-Cycloserine 239 is a well-known antibiotic which inhibits alanine racemase and D-alanyl-D-alanine ligase [117]. The reactivity of the y-lactam carbonyl towards nucleophilic reagents is enhanced by the electronegative oxygen substituent. 

Complexes of D-Cycloserine and Related Amino Acids with Antibiotic Properties... 

The bacterial cell wall is the first line of defense against environmental stress in gram-positive bacteria. Thus, selection schemes that change the cell wall structure can potentially make cells more resistant to environmental stress. D-cycloserine is an antibiotic that inhibits alanine racemase and D-alanine D-alanine ligase, both involved in cell wall biosynthesis. Mutants resistant to this antibiotic have been isolated in a number of gram-positive species and shown to have differences in surface properties (Clark Young, 1977 Reitz, Slade, Neuhaus, 1967). We have used D-cycloserine as a selective agent to directly select mutants in a variety of strains and found that the mutants obtained have properties useful in industrial fermentation processes. 

Another example is IM 2, the presence of which was originally described In cultures of Cycloserine producer Strepiomyces sp. FRl-5 by Yanagimoto (16). IM-2 induces blue pigment production and the shift of produced antibiotics from D-cycloserine to nucleoside antibiotics, such as showdomycin and minimycin (17). We purified lM-2 and determined its structure (18), as shown in Figure 5. 

A few antibiotics that are produced by Streptomyces spp. have structural affinities to single amino acids. Thus D-cycloserine (oxamycin), which has the structure XXVIII, could formally be obtained from D-serine amide by removal of the elements of water, or from D-alanine by an oxidative process. 

D-cycloserine is a competitive inhibitor of both the alanine racemase which catalyses the reversible interconversion of the two optical antipodes (L-alanine - D-alanine) and of the D-alanyl-D-alanine synthetase. Consequently, D-cycloserine blocs the synthesis of the muramyl nucleotide precursor (Fig. 4) at an early stage and induces the accumulation of the incomplete precursor UDP-MurNAc-Xi-y-D-Glu-Xa which lacks the essential terminal D-alanyl-D-alanine dipeptide. It is believed that the molecular basis for the D-cycloserine inhibition lies in the structural analogy between the antibiotic and D-alanine (Fig. 7)... 

Fig. 7. Molecular basis for antibiotic actions of D-cycloserine and penicillin.

Interactions with enantiomeric cycloserines. The antibiotic D-cycloserlne (if-aminoisoxazolidone-3) irreversibly inhibits,in bacteria certain enzymes metabolizing D-amino acids. In eucarlotes, the L-enantiomer (and DL-cycloserine) are the potent inactivators of transaminases and some other PLP-enzymes acting on structurally analogous L-amino acids. As demonstrated earlier by our colleagues H.Karpeisky, R.Khomutov, E. Severin et al.,27-29 the following steps appear to be in-... 

To investigate the role of minDSL in antibiotic resistance, the D-cycloserine resistant assay was performed. The results are in fig. 4. 

Cycloserine is a broad-spectrum antibiotic produced by Streptomyces orchidaceus. It is structural analogue of d-alanine and acts through a competitive inhibition of the... 

During the biosynthesis of the cell wall, the muropeptide is formed from acetylmuramyl-pentapeptide, which terminates in a D-alanyl-D-alanine. The synthesis of this precursor is inhibited by the antibiotic cycloserine (9.36), a compound produced by many Streptomyces fungi but which is not used clinically. During the crosslinking of the pen-tapeptide precursor, the terminal fifth alanine must be split off by a transpeptidase enzyme. This last reaction in cell wall synthesis is inhibited by the p-lactam antibiotics. 

Cycloserine is an inhibitor of cell wall synthesis and is discussed in Chapter 43 Beta-Lactam Antibiotics Other Inhibitors of Cell Wall Synthesis. Concentrations of 15-20 jrg/mL inhibit many strains of M tuberculosis. The dosage of cycloserine in tuberculosis is 0.5-1 g/d in two divided doses. Cycloserine is cleared renally, and the dose should be reduced by half if creatinine clearance is less than 50 mL/min. 

Cycloserine (seromycin) is a broad-spectrum antibiotic that is used with other drugs in the treatment of tuberculosis when primary agents have failed. Cycloserine is D-4-amino-3-isoxazolidone. 

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