Resistance to trimethoprim and sulfonamides

Abstract

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 druginsensitive 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 drugresistant but also less efficient (increased K m s) 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. sulfonamides / trimethoprim / resistance / plasmid / chromosomeRésumé -Résistance au triméthoprime et aux sulfamides.Les sulfamides et le triméthoprime ont été utilisés pendant plusieurs décennies en tant qu'agents antibactériens efficaces et bon marché, chez l'animal et chez l'homme.Cependant, la résistance à ces deux agents s'est propagée largement et rapidement.Ceci a surtout été dû à la propagation horizontale de gènes de résistance exprimant des variants des enzymes cibles dihydropteroate synthase et dihydrofolate réductase insensibles aux sulfamides et triméthoprime, respectivement.Deux gènes, sul1 et sul2, portés par des transposons et des plasmides, et exprimant des dihydropteroate synthases hautement résistantes aux sulfamides, ont été trouvés.Pour le triméthoprime, une vingtaine de gènes de résistance, phylogénétiquement séparés, exprimant des dihydrofolates réductases insensibles à l'antibactérien, ont été caractérisés.Ils se