Hatem E. Mohamed

 

BCH:561

Antibiotic resistance

Widespread resistance problems exist today in a global sense because the incorporation of antibiotics with a high resistance potential into animal feeds and because of the uncontrolled use of antibiotics with a resistance potential in the clinical setting. The proven targets for the main ant microbial drugs are cell wall biosynthesis, protein synthesis and DNA replication and repair, almost all have been developed resistant against their drugs. In DNA replication, one group of enzymes have proved to be effective target for therapeutic agents, which is topoisomerases enzymes, they are present in both prokaryotes and eukaryotes, where in eukaryotes they are targets for antitumour agents. In bacteria, DNA gyrase is one of the famous target among topoisomerases. DNA gyrase is an essential bacterial enzyme, catalyzes the ATP-dependent negative super-coiling of double-stranded closed-circular DNA. It consists of two subunits, gyrA and gyrB. GyrA has an N-terminal domain (59-64 KDa) involved in DNA breakage and reunion, while C-terminal (33 KDa) has a role in DNA protein interaction. GyrB consists of an N-terminal domain (43Kda) containing the ATPase activity, and a C-terminal (47Kda) interacts with both gyrA and DNA. There are two main groups of antibiotics targeting topoisomerases. The first is natural product antibiotics, Coumarine that inhibits DNA gyrases by competing with ATP for binding to the enzyme at GyrB subunit. The second, completely synthetic antibiotics are the fluoroquinolones, which are extremely potent. These react with N-terminal of gyrA to inhibit DNA segregation and induce irreversible DNA damage.

The future of clinical use of quinolones is shadowed by the recent development of resistance, which generally results from mutations in the structural genes of the target enzymes. This is one of the most potent antibiotics resistant strategies. The two other mechanisms are decreasing the accumulation and/or destroying the antibiotics. In case of Gyrases, almost all resistant strains have one mutation in GyrA or GyrB or two mutations in both subunits. In Mycobacterium tuberculosis was found two mechanisms for resistance, by producing mutation in GyrB and altering the levels of intracellular accumulation of drugs. In E. coli, a previously described clinical isolate has mutation in gene encoding for gyrA subunit (gly81asp) resistant to fluoroquinolones but susceptible to nalidixic acid, and then a spontaneous E. coli mutant was isolated from the first one, it has (asp82 glu) in addition (gly81asp), which becomes resistant to nalidixic acid too. Staphylococcus aureus developed resistant to cyclothialidine by mutation mapped in GyrB subunit near to ATP and coumarine binding sites. Mutant resistant to cinodine was isolated which exhibited an enhanced sensitivity to nalidixic acid. So, it is apparent that some ant microbial agent have cross resistant while others not. Generally, antibiotics affected by a single mutation are those for which the mutation occurs in their preferred target.

Antibiotic resistant microbes against therapeutic agents targeting DNA gyrase have been overcome by mutating the gene encode the target protein. So, the cell has a mechanism to sense the existing drug followed by correction mechanism. This process might be inherited by some how in the genetic apparatus of these microbes. It is possible to be a feedback mechanism, where signals molecules could play major role in controlling such mechanism. It is very precise and accurate in the resulted resistant. Specifically, in prokaryotes, no compartment organization, this means that, gyrase and ant microbial agent; gyrase and their DNA; transcription of the gyrase genes, and finally gyrase translation are take place in the cytoplasm. This indicating that these processes are in close contact with each other and might be signally connected. So, even if this mechanism of resistance is product of natural selection, it must be based on genetic mechanism already exist in the cell, which lead to such mutation. Such mechanism can provide bitter alternative to produce drugs act on disrupting the signal providing resistance.

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