Antibacterial agents nucleic acid synthesis inhibition

This class of substances inhibiting nucleic acid synthesis is often found in tissue culture cells to cause chromosome breakage and oflier alterations in the nucleus and nucleolus. They have been selected and studied because they ate powerful antibacterial or antitumour agents. Except for local applications, they are not of great therapeutic use, since they are very toxic. It is difficult to conceive a substance of this type, which would have a selective action because the most regular and vital feature of any type of cell is the presence of a double-stranded DNA, functioning normally. 

Several other studies were concerned with the effect of antibacterial and antifungal agents on nucleic acid synthesis. For example, nalidixic acid was noted to cause a transient inhibition of RNA, DNA and protein synthesis in cells of S. cerevlslae. Lomofungin was found to have a specific inhibitory effect on synthesis of both rlbosomal and messenger RNA precursors in protoplasts of Saccharomyces spp.° It also was inhibitory for purified Escherichia coli DNA-dependent RNA polymerases. ... 

Mechanism of Action. Pyrimethamine blocks the production of folic acid in susceptible protozoa by inhibiting the function of the dihydrofolate reductase enzyme. Folic acid helps catalyze the production of nucleic and amino acids in these parasites. Therefore, this drug ultimately impairs nucleic acid and protein synthesis by interfering with folic acid production. The action of sulfadoxine and other sulfonamide antibacterial agents was discussed in Chapter 33. These agents also inhibit folic acid synthesis in certain bacterial and protozoal cells. 

Early workers [29] found that, like benzylpenicillin, vancomycin, ristocetin and bacitracin, novobiocin caused an excessive accumulation of cell wall precursor, uridine diphosphate-7V-acetylmuramic acid-L-alanine-D-glutamic acid-L-lysine-D-alanine-D-alanine (UDP-MurNAc-L-ala-D-glu-L-lys-D-ala-D-ala) in Staph, aureus and it was thus considered that novobiocin was a specific inhibitor of peptidoglycan synthesis with an effect similar to that of penicillin. However, subsequent studies led to the withdrawal of this hypothesis [26], since novobiocin caused the accumulation of other precursor-type compounds and also strongly inhibited both nucleic acid and protein synthesis in this organism. Thus, accumulation of particular precursors does not necessarily reflect the site of action of an antibacterial agent [30]. 

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