Mutations, antimicrobial resistance

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. 

Adaptation Any soluble agent that affects a microorganian s life has the potential to set iq) conditions where the microbial cells adapt or mutate into resistant types. This is bad in almost all settings but clearly should not be tolerated in ahealtbcare facility. Use of standard disinfectants or sanitizers call for a rinse after the desired contact time. This is to minimize the risks associated with sub-lethal levels of the antimicrobial being present and risking adaptation or other forms of resistance. 

Antimicrobial resistance traits are genetically coded and can either be intrinsic or acquired. Intrinsic resistance is due to innately coded genes which create natural insensitivity to a particular antibiotic. Innate resistance is normally expressed by virtually all strains of that particular bacterial species. Acquired resistance is gained by previously susceptible bacteria either through mutation or horizontally obtained from other bacteria possessing such resistance via transformation, transduction, or conjugation. Acquired resistance is limited to subpopulations of a particular bacterial species and may result from selective pressure exerted by antibiotic usage. 

In those patients for whom prior eradication therapy has been unsuccessful or in individuals who exhibit antimicrobial resistance, quadruple therapy may be contemplated. Diagnosis of clarithromycin resistance can be done by sequencing the specific region of the 23S RNA where a point mutation results in prevention of drug binding. 

Bacteria can develop resistance to antimicrobial agents as a result of mutational changes in the chromosome or via the acquisition of genetic material (resistance genes carried on plasmids or transposons or the recombination of foreign DNA into the chromosome) (Fig. 2). 

Chromosomal resistance develops as a result of spontaneous mutation in a locus that controls susceptibility to a given antimicrobial drug the presence of the drug serves as a selecting mechanism to suppress susceptible organisms and favor the growth of drug-resistant mutants. In addition, extrachromosomal resis-... 

Dihydrofolate reductase (DHFR), a classic target in antimicrobial and anticancer chemotherapy, has been shown to be a useful therapeutic target in plasmodium, toxoplasma, and eimeria species. Pyrimethamine is the prototypical DHFR inhibitor, exerting inhibitory effects in all three groups. However, pyrimethamine resistance in P falciparum has become widespread in recent years. This is largely attributable to specific point mutations in P falciparum DHFR that have rendered the enzyme less susceptible to the inhibitor. 

We have already described that a number of rhizobial LPS mutants are sym-biotically defective because they likely induce an increased defense response by the host and/or are more sensitive to the host defense response. One structural feature of rhizobial LPS that appears to be important is the presence of OPS since its absence appears to result in a more robust plant defense response. We have also suggested (above) that the lack of OPS exposes the anionic COS on the bacterial surface which may make the rhizobial cell more sensitive to antimicrobial cationic peptides. Recent work in our laboratory (Brown, unpublished) has shown that a mutation of R. leguminosarum biovar viciae 3841 which specifically results in the loss of GalA residues from the core increases resistance to cationic peptides. It has also recently been shown that R. etli CE3 mutants in IpxE and IpxF, which are unable to remove the 1 and 4 -phosphates and, therefore have LA with increased anionic character, show increased sensitivity to cationic peptides (Ingram et al., 2010). 

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. 

To prevent the rapid development of bacterial resistance. Erythromycin and rifampin are used in combination in the treatment of foals with Rhodococcus (R.) equi infections. Each drug has a completely different mechanism of antimicrobial action their combination reduces the chance of chromosomal mutations conferring bacterial resistance. 

In bacteria, mutation is an important mechanism by which resistance to antibiotics and other antimicrobial chemicals is achieved, although the receipt of entirely new genes directly from other bacteria is also clinically very important. Spontaneous mutation rates (rates not influenced by mutagenic chemicals or ionizing radiation) vary substantially depending on the gene and the organism in question, but rates of 10-5-10-7 are typical. These values... 

Knowledge of the mechanisms of action of antimicrobial agents is required for understanding resistance acquired through chromosomal mutation and selection, and forms the basis of selecting antimicrobials for concurrent use, either as combination preparations or separately. 

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