Chromosomal Acquired

Acquired resistance. This occurs when bacteria which were previously susceptible become resistant, usually, but not always, after exposure to the antibiotic concerned. Intrirrsic resistance is always chromosomally mediated, whereas acquired resistance may occirr by mutations in the chromosome or by the acquisition of genes coding for resistance ftom an external source normally via a plasmid or transposon. Both types are clinically important and can result in treatment failure, although acquired resistance is more of a threat in the spread of antibiotic resistance (Russell Chopra 1996). 

Three genetic elements are responsible for acquired resistance chromosomes, plasmids and trarrsposons (Lewis 1989). Each of these will be considered in tiun. 

The molecular basis of acquired chromosomal resistance for specific antibiotics is discussed later in this chapter. 

Plasmids have the ability to transfer within and between species and can therefore be acquired from other bacteria as well as a consequence of cell division. This property makes plasmid-acquired resistance much more threatening in terms ofthe spread of antibiotic resistance than resistance acquired due to chromosomal mutation. Plasmids also harbour transposons (section 2.1.3), which enhances their ability to transfer antibiotic resistance genes. 

A second mechanism of acquired resistance to fosfomycin involves chromosomal mutations in sugar phosphate uptake pathways which are responsible for transporting fosfomycin into the cell. The alterations decrease accumulation of the antibiotic to levels below those required for inhibition. 

Acquired resistance to polymyxins in E. coli occurs because of chromosomal mutations which cause incorporation of aminoethanol and aminocarabinose in lipo-polysaccharide (LPS) in place of phosphate groups. The altered LPS has a decreased ionic charge which results in lowered binding of polymyxin and thus an increase in resistance to this group of antibiotics. 

The mechanism of acquired resistance in Pseudomonas aeruginosa is different. Chromosomal mutations result in the increase of a specific outer membrane protein with a concomitant reduction in divalent cations. Polymyxins bind to the outer membrane at sites normally occupied by divalent cations, and therefore it is thought that a reduction in these sites will lead to decreased binding of the antibiotic with a consequent decreased susceptibility of the cell. 

Bacterial resistance to biocides (Table 13.2) is usually considered as being of two types (a) intrinsic (innate, natural), a natural property of an organism, or (b) acquired, either by chromosomal mutation or by the acquisition of plasmids or transposons. Intrinsic resistance to biocides is usually demonstrated by Gram-negative bacteria, mycobacteria and bacterial spores whereas acquired resistance can result by mutation or, more frequently, by the acquisition of genetic elements, e.g. plasmid- (or transposon-) mediated resistance to mercury compounds. Intrinsic resistance may also be exemplified by physiological (phenotypic) adaptation, a classical example of which is biofilm production. 

Both AML and ALL are presumed to arise from clonal expansion of a single arrested cell. As these cells expand, they acquire one and often more chromosomal aberration, including translocations, inversions, deletions, point mutations, and... 

Development of resistance to rifaximin is primarily due to a chromosomal one-step alteration in the drug target, DNA-dependent RNA polymerase. This differs from the plasmid-mediated resistance commonly acquired by bacteria to aminoglycoside antibiotics such as neomycin... 

The classification and nomenclature of the International System for Human Cytogenetic Nomenclature (ISCN, 1985) as applied to acquired chromosome aberrations is recommended. Score sheets giving the slide code, microscope scorer s name, date, cell number, number of chromosomes and aberration types should be used. These should include chromatid and chromosome gaps, deletions, exchanges and others. A space for the vernier reading for comments and a diagram of the aberration should be available. 

Since the late 1970s, Southern blot analysis has had greater applicability in linkage analysis and detection of acquired chromosomal rearrangements. Currently, this technique forms the basis of a majority of protocols used in the biopsy... 

As in cancer predisposing syndromes, these genetic alterations are sometimes carried in the germline. Among human tumours, heritable mutations are an exception. Most alterations are acquired in somatic life in the form of chromosomal translocations, deletions, inversions, amplifications or point mutations. Certain oncogenic viruses play important roles in a few human tumours. Examples are human papilloma-virus in cervical cancer and skin tumours, Ep-stein-Barr virus in nasopharyngeal carcinoma and Burkitt s lymphoma, and human T-cell leukaemia viruses (e.g. HTLV-I, HTLV-II) in T-cell leukaemia. 

Acquired resistance implies a change in the DNA of the bacteria that results in the appearance of new characteristic features. Such resistance is achieved in two ways mutation of chromosomes in bacteria or acquisition of new pieces of DNA (plasmid) that code for a function of resistance. 

Although most human cancers are acquired diseases, all types may occur in heritable or nonheritablc forms, and heritabiUty may be associated with a dominant or recessive expression at a single locus, or with a constitutional chromosome anomaly. The changes associated with inherited predisposition to cancer must involve genetic alterations or mutational events at the sites of chromosome anomalies. There is now evidence for this in retinoblastomas. 

In acquired malignancies, oncogene activity appears to occur in association with chromosomal rearrangement. There is some evidence that the cooperation of two or more oncogenes, acting in concert, or in sequence, may effect transformation of a normal stale to a malignant one. However, further studies are needed to clarify this siiuation. 

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