Mutational resistance

Chellappan S, Kiran Kumar Reddy GS, All A, Nalam MN, Anjum SG, Cao H, Kairys V, Fernandes MX, Altman MD, Tidor B, Rana TM, Schiffer CA, Gilson MK (2007) Design of mutation-resistant HIV protease inhibitors with the substrate envelope hypothesis. Chem Biol Drug Des 69 455... 

Streptomycin binds with specific proteins (S12) on 30 S subunits of ribosomes. A change in this protein as a result of a mutation makes the ribosomes unable to bind with streptomycin, which makes the organism resistant. Mutational resistance to streptomycin occurs frequently. Gentamicin, tobramycin, netilmicin, and amikacin bind with many regions on both subunits of the ribosomes, and therefore mutational resistance to them is not common. 

In human medicine, selection pressure is at its most intense in hospitals, where antibiotics are extensively used. The major cause of problems of antimicrobial resistance in humans arises from overuse of antimicrobials at therapeutic levels in humans. It is generally accepted that drug resistance that develops in a bacterium as a result of mutation is only of importance within the individual host and a single bacterial strain. Because the determinant is chromosomal, the resistance cannot be transferred between different bacterial species and genera. In addition, the mutationally resistant microorganism is not usually as viable as the wild ones hence once the selective antibiotic is removed from the environment, the proportions of the mutant decrease. If exposure to the antibiotic continues, however, the mutants can become life-threatening to the patient. It should be understood that the antibiotic does not induce the mutation. The mutant simply takes advantage of its fortuitous spontaneous appearance to flourish in the presence of a selected antibiotic. 

Viral infections pose a major health risk for the global population. Many viruses are readily transmitted through common activities. While some viral diseases are not serious, many viral conditions cause a patient to be more susceptible to other, more serious secondary infections. Complicating the treatment and prevention of viral infections is the fact that viruses readily mutate. New mutants, if viable as a virus, are often resistant to existing drug treatments. Because of the widespread mutational resistance observed in various viruses, new drugs for the treatment of viral diseases are continuously sought. 

Hirschberg, J. and L. McIntosh (1983). Molecular basis of herbicide resistance in Amaranthus hybridus. Science, 222 1346-1349. Hirschberg, J., A.B. Yehuda, I. Packer, and N. Ohad (1987). Mutations resistant to photosystems II herbicides. NATO ASI Series A (Plant Mol. Biol.), 140 357-366. 

Point mutation tests have been developed also for cultured mammalian cells (de Marini et al, 1989). These tests are based on the mutational resistance to otherwise cytotoxic agents (i.e. TKor HPRT mutations, conferring resistance to trifluorothymidine and 6-thioguanine, respectively). Compared to the Ames test and other bacterial assays they are, however, more laborious and time consuming. 

The complete genetic code is shown in Figure 24.16. We can make several observations about the genetic code. First, methionine and tryptophan are the only amino acids that have a single codon. All others have at least two codons, and serine and leucine have six codons each. The genetic code is also somewhat mutation-resistant. For those amino acids that have multiple codons the first two bases are... 

Intrinsic resistance, mutational resistance, and plasmid-mediated resistance. 

This phenomenon involve the passing of mutational resistance information from one organism to another. Altered DNA, which confers resistance, is packaged into a plasmid, which can then be transferred to other organisms. 

T. I. Nicas and R. E. W. Hancock, Outer membrane protein HI of Pseudomonas aeruginosa involvement in adaptive and mutational resistance to ethylenediaminetetraacetate, polymyxin B, and gentamicin, J. Bacterial, 143 (1980) 872-878. 

HIV ResistDB http //resdb.lanl.gov/Resist DB/default.htm HIV mutations resistant to anti-HIV drug... 

Several scenarios exist for which continuous bioreactors are feasible and preferred, snch as high volnme production, use of mutation-resistant bacteria cnltnre, wastewater treatment, and processes that do not require a sterile environment. Cnrrently, continnons bioreactors are used for the production of vinegar, baker s yeast, alcohols, and solvents, and for wastewater treatment (Bellgardt, 2000b Simon et al., 2006 Williams, 2002). Proper control systems also allow continnons principles to be nsed in other production systems. These requirements inclnde that the process does not necessitate a sterile environment or that it can be easily controlled throngh alternative means such as flocculation, substrate and... 

The photochemical activity of resistant biotype seems to be significantly affected by polypeptide D1 mutation. Resistant biotype is at a disadvantage in intra-species competition indeed, without herbicide treatments, resistant biotype disappears from wild population. The decrease of the electron transfer kinetic constant between QA and QB seems to be one of the most important factor for resistant biotype competitiveness decrease. 

A remarkable property of vancomycin has been the long delay in the emergence of resistance in susceptible species. The unusual mechanism of activity of vancomycin is often cited as the reason that mutational resistance is essentially unknown. The first well-documented reports of vancomycin resistance appeared only in 1988 (8,9). Resistance appeared in the enterococci, and it was mediated by plasmids carrying nine new genes, probably the most complex mechanism of resistance seen to date (10,11). 

This molecular mechanism is part of what makes the glycopepcide class attractive as antibacterial agents. The interaction with the precursor is highly specific, and as no eukaryotic analog of o-alanyDo-alanine is present in mammalian cells, no basis for mechanism-based toxicity is present. The mechanism also seems to be one for which mutational resistance should be relatively difficult to achieve, as the D-alanyl-D-alanine-con-taining pentapeptide is the result of several synthetic steps in precursor formation, and it is involved in several steps of wall synthesis. 

Katsu T, Kuroko M, Morikawa T, Sanchika K, Yamanaka H, Shinoda S, Fujita Y. Interaction of wasp venom mastoparan with biomembranes. Biochim Biophys Acta 1990 1027 185-190. Nicas Tl, Hancock REW. Outer membrane protein HI of Pseudbtnoiuu aetmmosa Involvement in adaptive and mutational resistance to cthylenediaminetetraacetate, polymixin B, and gentamicin. ] Bacieriol 1980 143 872. 

Darunavir is the most recently approved HIV PI (DRV, TMC-114, UIC-94017, trade name Prezista) (Koh, 2003). This compound, developed by Tibotec, retains its activity even toward highly mutated resistant PR species. Interestingly, DRV might bind not only to the active site but also to a surface pocket in the flaps of HIV PR, and it could also inhibit dimerization of the PR (Koh, 2007 Kovalevsky, 2006,2008). A number of mutations in the HIV PR are apparently needed to render the enzyme resistant toward DRV. Saskova et al. (2008) recently characterized a virus strain isolated from an HIV-positive patient under DRV treatment that harbored 22 mutations in the PR region and was highly resistant toward the drug. 

After mutation, there is a phase of mutation expression. Mutation expression is very relevant in systems based on the induction of resistance mutation. Resistance at the permease level can be expressed only after functional permeases have been diluted out of the membrane this applies to canavanine or other types of analogue systems. 

Adaptation," Mutations, Resistance, Immunity, and Chemotherapy, and Enzyme Problems (Sevag). VI 33... 

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