Resistance to Antibiotics, Genetics of SB Levy, Tufts University School of Medicine, Boston, MA, USA
© 2001 Elsevier Inc. All rights reserved.
This article is reproduced from the previous edition, volume 3, p 1687, © 2001, Elsevier Inc.
Bacteria emerge with antibiotic resistance by a variety of mechanisms. A mutation in the gene for the target for the anti biotic may occur spontaneously or in response to environmental mutagens, which provides the bacteria with a gene product that is no longer susceptible to the antibiotic. Examples of this kind of resistance include the mutated RNA polymerase enzyme providing resistance to rifampicin; mutated ribosomal proteins causing resistance to streptomycin; mutations in the topoisome rase II (gyrase) enzyme leading to resistance to quinolones; and mutation in the membrane-associated penicillin-binding pro teins which mediate resistance to the activity of penicillin. A second mechanism is the overexpression of genes that destroy the antibiotic or substitute for its target. An example of this is the AmpCβ-lactamases among the Enterobacteriaceae in which overproduction of this normal cell product provides resistance to a broad spectrum of β-lactam (penicillin-like) antibiotics, or the overexpression of a precursor peptide of the cell wall, the target of vancomycin, which leads to resistance to vancomycin in Staphylococcus aureus. In some cells, resistance is provided by the increased expression of cell efflux pumps, which normally function for other purposes, but that can also pump out multiple antibiotics. The most common way for a bacterium to become resistant is to acquire resistance genes from other bacteria. There are many mechanisms available by which resistance genes are exchanged. Cells may pick up naked DNA in the environment and incorporate it into their chromosome by a process called ‘transformation’. Resistance genes from one bacterium may enter another via bacteriophages (bacterial viruses) in what is called ‘transduction’. The transfer of circular extrachromosomal pieces of DNA (plasmids) from one organism to another by cell-to-cell contact is called ‘conjugation’. Transposition is the movement of small pieces of DNA (transposons) from one DNA vehicle to another, such as from phages to the chromo some or from a plasmid to the chromosome. This process
fosters the stabilization of the resistance gene into new DNA molecules. Some transposons themselves can move among bacteria; these are called ‘conjugative transposons’. A unique kind of transposon, the ‘integron’, has more recently been described. It involves a group of resistance genes that reside together within a usually inactive transposon. The important feature of the integron is the gene int (integrase), which allows cassettes of resistance genes to be incorporated into a specific site near a promoter, a DNA sequence that allows the gene to be expressed. Many different types of bacteria have become multidrug resistant using the integron mechanism. The origin of resistance genes is not known, but it has been proposed that they evolve from protective traits of the antibiotic-producing organisms themselves. Resistance genes mediate resistance in the following ways: by inactivating the antibiotic, for example, as penicillinases do to penicillins; by substituting new, insensitive target enzymes, as in the mechan isms for resistance to trimethoprim and sulfonamides; by altering targets, as for erythromycin and tetracyclines; or by altered transport, chiefly exemplified by efflux pumps, which keep single or multiple antibiotics out of the cell. Some resistance genes require other changes in the host bacterium in order to produce their resistance. This feature has been clearly shown for methicillin resistance mediated by the mec gene which alone provides very little resistance. It must be accompanied by mutations in other chromosomal genes in order to express fully fledged resistance. The same may be said for changes in the membrane to accommodate new efflux proteins. It is highly likely that other kinds of genetic mechanisms for resistance will emerge as scientists continue to study antibiotic resistance and to decipher the genetic code of an increasing number of bacteria.
See also: Antibiotic Resistance; Antibiotic-Resistance Mutants; Bacterial Transformation.
Brenner’s Encyclopedia of Genetics, 2nd edition, Volume 6