Replication of Bacterial DNA

Table 33—4 lists drugs that exert their primary antibacterial effects by impairing the synthesis and replication of bacterial DNA and RNA. These agents are presented here. 

Replication of bacterial DNA with an integrated F factor. There are two origins of DNA replication, ori - and ori . Replication is bidirectional from ori - and unidirectional from orl . Somehow the cell solves this topological dilemma when cell division occurs. 

Pharmacology The fluoroquinolones are synthetic, broad-spectrum antibacterial agents that inhibit DNA gyrase and topoisomerase IV. DNA gyrase is an essential enzyme that is involved in the replication, transcription, and repair of bacterial DNA. Topoisomerase IV is an enzyme known to play a key role in the partitioning of the chromosomal DNA during bacterial cell division. 

Cidal effects can be a result of the disruption of the cell wall or membrane. Cell lysis may occur when water diffuses into the high-osmolarity bacterial cytosol through the antibiotic-induced holes in the membrane, causing the bacteria to swell and burst. Cidal effects also can occur as a consequence of inhibition of bacterial DNA replication or transcription. 

Adds a section on the "replication factories" of bacterial DNA Includes latest perspectives on DNA recombination and repair... 

Multiple replicons In eukaryotes, replication of chromosomal DNA occurs only in the S phase of the cell cycle. As for bacterial DNA (see Topic F3), eukaryotic DNA is replicated semi-conservatively. Replication of each linear DNA molecule in a chromosome starts at many origins, one every 3-300 kb of DNA depending on the species and tissue, and proceeds bi-directionally from each origin. The use of multiple... 

The replication of a linear DNA molecule in a eukaryotic chromosome creates a problem that does not exist for the replication of bacterial circular DNA molecules. The normal mechanism of DNA synthesis (see above) means that the 3 end of the lagging strand is not replicated. This creates a gap at the end of the chromosome and therefore a shortening of the double-stranded replicated portion. The effect is that the chromosomal DNA would become shorter and shorter after each replication. Various mechanisms have evolved to solve this problem. In many organisms the solution is to use an enzyme called telom-erase to replicate the chromosome ends (telomeres). 

Question A eukaryotic cell contains 1,000 times the amount of DNA of a bacterial chromosome. How can replication of eukaryotic DNA be accomplished within the period of the S phase (a few hours) ... 

The answer is e. (Murray, pp 452-467. Scriver, pp 3-45. Sack, pp 1-40. Wilson, pp 101-120.) Puromycin is virtually identical in structure to the 3 -terminal end of tyrosinyl-tRNA. In both eukaryotic and prokaryotic cells, it is accepted as a tyrosinyl-tRNA analogue. As such, it is incorporated into the carboxy-terminal position ol a peptide at the aminoacyl (A) site on ribosomes, causing premature release of the nascent polypeptide. Thus, puromycin inhibits protein synthesis in both human and bacterial cells. Streptomycin, like tetracycline and chloramphenicol, inhibits ribosomal activity. Mitomycin covalently cross-links DNA, which prevents cell replication. Rifampicin is an inhibitor of bacterial DNA-dependent RNA polymerase. 

The alkylation of the ITQ nucleus of general formula 429 is reported in a patent as well as the parent compounds 357 (see Sect. 5.2) [140]. They were prepared as inhibitors of bacterial DNA synthesis and replication. As the parent benzisothiazolones, a mixture of N- and 0-alkyl derivatives 430 and 431 (major isomer) was obtained performing the reaction in DMF and CSCO3 at 25 °C (Scheme 101). 

Although eukaryotic nuclear DNA is linear, long loops of DNA are fixed in place within chromosomes (Chapter 10). Thus torsional stress and the consequent formation of su-percolls also could occur during replication of nuclear DNA. As in bacterial cells, abundant topoisomerase I in eukaryotic nuclei relieves any torsional stress in nuclear DNA that would develop in the absence of this enzyme. 

Many drugs used in medicine to treat bacterial infections are targeted to interfere with their ability to synthesize RNA and proteins. Thus, medical students need to know the basics of bacterial DNA replication, RNA synthesis, and protein synthesis. 

A number of differences between eukaryotes and prokaryotes affect the processes of replication, transcription, and translation, in addition to the content of their DNA. Eukaryotic DNA is complexed with histones, and prokaryotic DNA is not. In eukaryotic cells, the process of transcription, which occurs in the nucleus, is separated by the nuclear envelope from the process of translation (protein synthesis from the mRNA template), which occurs in the cytoplasm. Because prokaryotes lack nuclei, the processes of transcription and translation occur simultaneously. Transcription of bacterial DNA requires only one promoter per operon. In contrast, human DNA requires one promoter for each gene. 

Norfloxacin 243 is one of oral broad-spectrum fluoroquinolone antibacterial agents used in the treatment of certain infections caused by bacteria, such as gonorrhea, prostate, and urinary tract infections. The mechanism of action of 243 involves inhibition of the A subunit of bacterial DNA gyrase, an enzyme which is essential for DNA replication. ... 

Engel ML, Ray DS. The kinetoplast structure-specific endonuclease 1 is related to the 5 exo/endonu-dease domain of bacterial DNA polymerase I and colocalizes with the kinettqrlast topoisomerase II and DNA polymerase beta during replication. Proc Nad Acad Sd USA 1999 96(15) 8455-60. 

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