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 bot h has, however, spread extensively and rapidly. This is mainly due to the h orizontal 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 syntha ses highly resistant to sulfonamide, have been found. For trimethoprim, alm ost twenty phylogenetically different resistance genes, expressing drug-ins ensitive dihydrofolate reductases have been characterized. They are efficie ntly spread as cassettes in integrons, and on transposons and plasmids. One particular gene, dfr9, seems to have originally been selected in the intes tine of swine, where it was found in Escherichia coli, on large plasmids in a disabled transposon, Tn5393, originally found in the plant pathogen Erwi nia amylovora. There are also many examples of chromosomal resistance to su lfonamides and trimethoprim, with different degrees of complexity, from sim ple base changes in the target genes to transformational and recombinationa l exchanges of whole genes or parts of genes, forming mosaic gene patterns. Furthermore, the trade-off, seen in laboratory experiments selecting resis tance mutants, showing drug-resistant 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 susceptibilit y will not return after suspending the use of sulfonamide and trimethoprim.