Resistance to trimethoprim and sulfonamides.
Sulfonamides and trimethoprim have been used for many decades as efficient and inexpensive antibacterial agents for animals and man. Resistance to both has, however, spread extensively and rapidly. This is mainly due to the horizontal spread of resistance genes, expressing drug-insensitive variants of the target enzymes dihydropteroate synthase and dihydrofolate reductase, for sulfonamide and trimethoprim, respectively. Two genes, sul1 and sul2, mediated by transposons and plasmids, and expressing dihydropteroate synthases highly resistant to sulfonamide, have been found. For trimethoprim, almost twenty phylogenetically different resistance genes, expressing druginsensitive dihydrofolate reductases have been characterized. They are efficiently spread as cassettes in integrons, and on transposons and plasmids. One particular gene, dfr9, seems to have originally been selected in the intestine of swine, where it was found in Escherichia coli, on large plasmids in a disabled transposon, Tn5393, originally found in the plant pathogen Erwinia amylovora. There are also many examples of chromosomal resistance to sulfonamides and trimethoprim, with different degrees of complexity, from simple base changes in the target genes to transformational and recombinational exchanges of whole genes or parts of genes, forming mosaic gene patterns. Furthermore, the trade-off, seen in laboratory experiments selecting resistance mutants, showing drug-resistant but also less efficient (increased Kms) target enzymes, seems to be adjusted for by compensatory mutations in clinically isolated drug-resistant pathogens. This means that susceptibility will not return after suspending the use of sulfonamide and trimethoprim.
Sköld
O
O
Division of Microbiology, Department of Pharmaceutical Biosciences, Biomedical Center, Uppsala University, Sweden. Ola.Skold@farmbio.uu.se
D000818:Animals; D002875:Chromosomes; D004352:Drug Resistance, Microbial / Q000235:genetics*; D022761:Gene Transfer, Horizontal; D006801:Humans; D008956:Models, Chemical; D010957:Plasmids; D015183:Restriction Mapping; D013449:Sulfonamides / Q000627:therapeutic use*; D014295:Trimethoprim / Q000627:therapeutic use*; D014296:Trimethoprim Resistance / Q000235:genetics*
D013449:Sulfonamides; D014295:Trimethoprim