Mutations resistance mechanisms

Acquired resistance has been observed by constitutive upregulation of mdr efflux pump expression due to a mutation inactivating a respective repressor or inducibly, caused by molecules transiently inactivating repressor molecules upon binding. Depending upon the substrate spectra of the respective subset of efflux pumps upregulated, a multiple drug resistance (mdr) phenotype is expressed, which in combination with a specific resistance mechanism can contribute to a clinically relevant level of resistance. 

A number of skin diseases, mainly characterized by blistering, have been found to be due to mutations in genes encoding various keratins. Three of these disorders are epidermolysis bullosa simplex, epidermolytic hyperkeratosis, and epidermolytic pahnoplantar kerato-derma. The blistering probably reflects a diminished capacity of various layers of the skin to resist mechanical stresses due to abnormalities in microfilament strucmre. 

The most common mechanism of isoniazid resistance is the mycobacteria s formation of mutations in catalase-peroxidase KatG, the enzyme that is responsible for activation of isoniazid. Another resistance mechanism is through a missense mutation related to the inhA gene involved in mycolic acid biosynthesis. 

Influenza virus resistant to oseltamivir has not been found in naturally acquired isolates but has been isolated from influenza patients who have undergone treatment with this drug. These resistant strains contain mutations in the active site of neuraminidase and are generally less virulent and infective than nonresistant virus. In vitro passage of influenza virus in the presence of oseltamivir carboxylate can produce mutations in hemagglutinin that decrease the overall dependence of viral replication on neuraminidase however, the clinical relevance of this resistance mechanism is unknown. 

One possibility is that there is differential susceptibility to both mutation and killing among the cells. If, for example, there are two populations of cells, the high-dose data reflect the mutation rate of the component more resistant to killing. If these cells are also resistant to mutation, the resistance of the total cell population is underestimated. Another possibility is that there is a mutation-repair mechanism that is turned on at high doses. Deviations from either of these causes can usually be detected by the shape and slope of the curve at high doses for example, linear extrapolation from high-dose... 

Bacteria can obtain the various types of resistance mechanisms described previously by undergoing modifications in their genetic constitution. Many bacteria simply inherit their resistance genes from their forerunners. In addition, genetic mutations can occur that can confer a new trait. For example, it has been estimated that bacteria undergo spontaneous mutation at a frequency of approximately 1 in 10 cells. These mutations can confer resistant traits to the subsequent progeny. Mutations are believed... 

Multidrug resistance (Mdr) is a serious problem in enteric and other Gramnegative bacteria [41, 71, 273-283] (Table 4.17). As distinct from plasmid-mediated resistance, described above, Mdr is a term employed to describe a resistance mechanism by genes that comprise part of the normal cell genome. These genes are activated by induction or mutation caused by some types of stress, considered below. Because the genes are ubiquitously distributed, there is no need for genetic transfer. 

Chen, M., Han, Z., Quiao, X., and Qu, M., Resistance mechanisms and associated mutations in acetylcholinesterases in Sitobion avenue (Fabricius), Pestic. Biochem. Physiol., 87,189, 2007... 

Epothilones retain significant activity against paclitaxel-selected cell lines that harbor a distinct set of tubulin mutations, and again this could perhaps translate into clinical utility in the treatment of Taxol-resistant tumors. However, any such predictions must be treated with great caution, as the clinical significance of individual resistance mechanisms identified in vitro has not been established. 

DMI resistance may be governed by different resistance mechanisms co-existing in the same isolate. Molecular detection tools can help to find low frequencies of mutated individuals in populations. However, since resistance to DMIs may be a combined effect of several mechanisms, the molecular results have to be treated with care and bioassays may be always needed for verification. 

Spontaneous mutation brings about organisms with novel antibiotic resistance mechanisms. If these cells are viable, in the presence of the antimicrobial agent selective multiplication of the resistant strain occurs so that it eventually dominates as above. 

Smital, T. and Kurelec, B. (1998) The chemosensitizers of multixenobiotic resistance mechanism in aquatic invertebrates a new class of pollutants. Mutat. Res., 399, 43-53. 

Waldmann, P., B. Pivcevic, W.E.G. Muller, R.K. Zahn and B. Kurelec. Increased genotoxicity of acetylaminofluorene by modulators of multixenobiotic resistance mechanism studies with the fresh water clam Corbiculafluminea. Mutat. Res. 342 113-123, 1995. 

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