Chromosome mutations

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. 

Two mechanisms of chromosomal resistance have been identified. A mutation of dihydropteroate synthetase (DHPS) in Strep, pneumoniae produces an altered enzyme with reduced affinity for sulphonamides. Hyperproduction of p-aminobenzoic acid (PABA) overcomes the block imposed by inhibition ofDHPS. The specific cause of PABA hyperproduction is unknown, though chromosomal mutation is the probable cause. 

Chromosomal mutations in E. coli result in overproduction of dihydrofolate reductase (DHFR). Higher concentrations of trimethoprim, which may not be therapeutically achievable, are therefore required to inhibit nucleotide metabolism. Other mutations lower the affinity of DHFR for trimethoprim. These two mechanisms of resistance may coexist in a single strain, effectively increasing the level of resistance to the antibiotic. 

Rifampicin is the semisynthetic derivative used widely in the UK. Resistance to rifampicin is primarily due to chromosomal mutations resulting in an altered RNA polymerase which is less well inhibited by the drug. The mutations tend to be clustered within short conserved regions of the J3 subunit gene of RNA polymerase. Similar mutations have been found in all bacterial species studied thus far. 

Chromosomal mutations have also been described which produce a modified translocation factor protein with lowered affinity for fusidic acid. 

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. 

Specific pathologic characteristics distinguishing Hodgkin s lymphoma from non-Hodgkin s lymphoma include morphology, cell surface antigens, and chromosomal mutations. 

Chromosomal mutations are recognised as morphological alterations in the gross structure of chromosomes, that is, they are structural aberrations which can be detected microscopically. Compounds which cause chromosome damage are called clastogens. 

In genotoxic assays, commercial hexane, consisting of -hexane and other six-carbon isomers, did not produce chromosomal mutations either in vitro or in vivo Results have generally been negative in bacterial assays and in other mammalian cell assays. Morphologic alterations in sperm were noted in one inhalation study in rats. ... 

Induction of morphological transformation of SHE cells can occur in the absence of detectable induction of gene mutations measured concomitantly in the same cells (Barrett et al, 1983). Diethylstilbestrol and asbestos are two examples of chemicals that incluce cell transformation but not gene mutations (Barrett et al, 1981, 1983). However, a gcxxl correlation is observed between induction of chromosomal mutations (numerical and structural changes) and induction of cell transformation (Barrett etol, 1983 Oshimiueerol, 1984). 

Vogel, E.W. (1989) Somatic cell mutagenesis in Drosophila-, recovery of genetic damage in relation to the types ofDNA lesions induced in mutationally unstable and stable X-chromosomes. Mutat. Res., 211, 153-170... 

Chromosomal mutation affects blocks of genes in one or more chromosomes. 

More than one-third of spontaneous abortions are caused by chromosomal and genomic mutations. Chromosomal mutations produce their effect mainly by predisposing the organism to transmit unbalanced combinations of chromosomes. 

One system uses mouse lymphoma cells and detects mutations that cause deficiency of thymidine kinase (TK). Another uses Chinese hamster cells and detects mutations in the gene that produces hypoxanthine-guanine phosphoribosyl transferase (HGPRT). Both tests cure efficient, are widely applied, and can be completed in a few weeks. Although not as simple, rapid, and efficient as the Salmonella tests, they have the advantage of being done in a eukaryote. Mammalian-cell cultures cure also used to test for chromosomal mutation. 

The best present basis for a partial assessment of the impact is dominant gene and chromosomal mutations, which constitute the major mutational impact in the next half-dozen generations. It is within the time span of only a few human generations that the preponderance of mutation impact will occur. 

---