J. Med. Microbiol. - Vol. 38 (1993). 157-159 0 1993 The Pathological Society of Great Britain and Ireland EDITORIAL . Mobile genetic elements in antibiotic resistance Chromosomally-mediated resistance, arising from of chromosome containing an origin of replication mutation during therapy or spread of a single or- with the subsequent acquisition of the genes we see ganism, can be a major contributor to the resistance today. This was, however, a very ancient event. encountered in bacterial infection. Chromosomal Resistance plasmids are similar to plasmids found in mutations may change membrane permeability, re- strains of gram-negative rods isolated before the ducing the efficacy of many antibacterial agents, antibiotic era that do not carry resistance mechanisms, induce the production of chromosomally encoded indicating that resistance genes must have been enzymes such as #?-lactamases, or alter the target acquired since the introduction of antibiotics into enzyme, e.g., dihydrofolate reductase (DHFR), the medi~ine.~How have plasmids accumulated such binding site of trimethoprim. The nature of these diversity of resistance genes? Some plasmids are not mechanisms is such that they can only be passed on essential for bacterial survival under normal circum- vertically to the progeny of the resistance organisms. stances; they are free to mutate without lethal effects Thus, they account for only a small proportion of on the cell. They can also move between cells and resistant isolates and generally mediate only low- species, accumulating genes by recombination. Homo- level resistance. Plasmid-mediated resistance accounts logous recombination, integration and excision from for most high-level resistance found in bacteria and the host chromosome must play some part in the has resulted in the rapid spread and accumulation of acquisition of genes by plasmids. However, trans- the most efficient resistance mechanisms with a con- position has been shown increasingly to be a major comitant challenge to antibacterial therapy. contribution to plasmid development since the first The evolution and spread of resistance plasmids has recognition of a transposon, Tnl, by Hedges and been promoted by the wide use of antibiotics in Jacob.' Complete and functional resistance genes can medicine and animal husbandry. In the presence of be transferred from one replicon to another by this antibiotics, the acquisition of a resistance plasmid by mechanism. the host cell is obviously beneficial. It will survive and Two major classes of transposon have been multiply, as will the plasmid, whilst non-plasmid identified ; class I or composite transposons and class carrying cells will be eliminated. Plasmids are passed I1 or complex transposons differ in structure and on vertically to the cell's progeny during cell division. function. They may originate from the use of modified However, many resistance plasmids are also capable of restriction endonucleases or recombinases which have mediating their transfer to other organisms, and acquired functions in recognition and recombination indeed to organisms of other species, by conjugation. of specific sequences. Class I transposons are a This greatly increases the potential for the spread of heterogeneous group of elements, carrying a variety of resistance genes situated on plasmids.The plasmid, resistance genes that share similar structural and which is separate from the cell in evolutionary terms, functional properties, but share little DNA homology.7 ensures its maintenance in the cell whether or not The class I1 transposons are more homogeneous, antibiotic selection pressure is present. Resistance comprising three different but related " families ", the plasmids seem to be stable in bacterial populations,' Tn3, Tn21 and Tn2.501 group^.*^^ Transposon 21 and even when there is no selective pressure; indeed their its group have been the most widely studied. These stability will benefit the progeny of the cell in future transposons usually carry more than one resistance encounters with the antibiotic, which may be likely in determinant ;'9 lo resistance to sulphonamide is usually the case of commonly used drugs. present ;the OXA and PSE #?-lactamasesare commons Most resistance plasmids mediate resistance to more as is enzymatic resistance to the aminoglycoside than one, sometimes as many as seven, antibiotim2 antibiotics." Resistance to mercury compounds12and Selective pressure applied by the use of a single trimethoprim resistance mediated by dhfr I1 and V are antibiotic will select for all the other resistance also associated with Tn2I.l3 The dhfr I gene which is mechanism^.^ Many outbreaks of plasmid-mediated usually associated with Tn7 has also been shown as resistance causing problems in hospital or clinical part of a Tn21-like transposon.14 environments have been documented and single or It is not immediately obvious how such a homo- closely related plasmids have often been shown to be geneous group of elements can harbour such a wide respon~ible.~ range of resistance mechanisms but it has been How have these problematic and promiscuous proposed that these structures were formed by the organelles evolved? Plasmids may have originated integration of discrete resistance elements into existing from an aberrant phage of from the excision of a piece transposons.10In these transposons, and plasmids that ~~ 157 11 JMM 38 1511 ELIITORIAL carry similar resistance mechanisms. e.g. R388 and ution of the integron, which has so far only been R46, highly conserved regions are found in sequences implicated in antibiotic resistance, seems also to have immediately surrounding the structural gene. Flanking been the result of antibiotic pressure. The use of many the structural gene are GTTA sequences which mark different antibiotics has resulted in the accumulation the insertion points for the resistance gene and of multiple resistance mechanisms on single plasmids represent recombination hot-spots necessary for cross- resulting in co-selection of different resistance over of resistance genes.’’ At the 5’-end of the mechanisms. The evolution of transposons, and resistance gene there is an open reading frame which perhaps integrons, allows flexibility in the genetic codes for a protein that shares homology with both response to a battery of antibiotics. transposon resolvases and phage site-specific S. TAIT integrases.I6 This integrase has been designated iizt or Department of Medical Microbiology, The Medical School, tnpP6 and is responsible for the recombination of UniLersitj of Edinburgh. Teviot Place, Edinburgh the resistance genes. At the 3’-end of the resistance gene is an imperfect palindromic region of 59 bp that is essential for control of integration and contains the References GTTA sequence which marks the point of excision.” A gene “cassette”. containing the resistance gene, 1. Bennett PM, Linton AH. Do plasmids influence the survival of the GTTA sequence and all but the last seven bases of bacteria? J Antimicrob Chernotlwr 1986: 18 Suppl C: 1 23- 126. the 59-bp region, has been proposed as the unit of 2. Foster TJ. Hasmid-determined resistance to antimicrobial recornbination.18 Circularisation of the element, after drugs and toxic metal ions in bacteria. Microbiol Reu 1983; excision from its original location, precedes its in- 47: 361409. 3. Amyes SGB, McMillan CJ, Drysdale JL. Transferable tegration in the new replicon.18 This small mobile trimethoprim resistance amongst hospital isolates. In: genetic element has been called an integron (In).16 The Grassi GG. Sabath LD (eds) New trends in antibiotics: GTTA and an incomplete 59-bp sequence have been research an therapy. New York, Elsevier/North-Holland Biomedical Press. 1981 : 325-327. identified in Tn7carrying the dhfrI gene. This gene has 4. Amyes SGB, Doherty CJ, Young H-K. High-levcl trimelhoprim also been characterised in Tn21 as part of an integron, resistance in urinary bacteria. Eur J Clin Microbioll986; 5: indicating an exchange between the two transposons.“ 287-29 1. 5. Datta N, Hughes VM. Plasmids of the same Inc groups in Evidence of an ancestral integron has been found in Enterobacteria before and after the medical use of the Pseudomonas aeruginosa plasmid pVS 1 ; this antibiotics. Nature 1983; 306: 616617. consists only of the integrase region and a single 6. Hedges RW, Jacob AE. Transposition of ampicillin resistance from RP4 to other replicons. Mol Gen Genet 1974; 132: GTTA cross-over point.Ig It has been proposed that 3 1-40. the sulphonamide resistance gene (sulI) was initially 7. Schmitt R. Molecular biology of transposable elements. J integrated into this region at the 3’-end of the integrase. Antimicrob Chemother 1986; 18 Suppl C: 25-34. 8. Lafond M, Couture F, Vezina G, Levesque RC. Evolutionary This reflects the early clinical use of the sulphonamides, perspectives in multiresistance #Mactamase transposons. J since the sul gene is almost completely conserved in Bacteriol 1989; 171 : 6423-6429. these structures. This has been followed by site-specific 9. Wiedemann B, Meyer JF, Ziihlsdorf MT. Insertions of re- sistance genes into Tn21-like transposons. J Antimiiroh integration, mediated by the integrase, of multiple Chemother 1986; 18 Suppl C: 85-92, resistance genes in the form of “cassettes” and the 10. Martinez E, de la Cruz F. Transposon Tn21 encodes a RecA- 59-bp region at the original GTTA cross-over point independent site-specific integration system. Mol Gen Gener 1988; 211 : 320-325. which has formed the modern integron. Other recombi-