Sulphonamide resistant commensal Neisseria with alterations in the dihydropteroate synthase can be isolated from carriers not exposed to sulphonamides

Three resistant clones were identified and the resistance phenotype could be explained by amino acid variations in their dihydropteroate synthase, the target molecule for sulphonamides. Some of these variations occurred in positions corresponding to previously detected variations in resistant N. meningitidis.Sulphonamide resistant commensal Neisseria were isolated from an environment not exposed to sulphonamides, suggesting that resistant Neisseria has become a natural part of the commensal throat flora.Sulphonamides inhibit the enzyme dihydropteroate synthase (DHPS) by acting as competitive inhibitors and thereby blocking the biosynthesis of folic acid in bacteria. We have earlier defined sulphonamide resistance in Neisseria meningitidis as amino acid variations in the chromosomal folP-gene, encoding DHPS [1]. The DHPS of the resistant strain 3976 had a Leu in position 31 and a Cys in position 194, instead of the Phe and Gly residues found in susceptible strains. These two alterations conferred sulphonamide resistance, but they also had a negative influence on substrate binding of the DHPS enzyme [2]. This disadvantage was compensated by an additional alteration in position 84, which improved the substrate binding without affecting the resistance. Such compensatory mutations can lead to irreversible resistance because the bacterium has little to gain in reverting to the susceptible state. This phenomenon can therefore explain the presence of sulphonamide resistant strains of N. meningitidis in an environment not exposed to sulphonamides.Horizontal gene transfer via natural transformation has been suggested as the main mechanism of genetic diversity among Neisseria [3]. Genetic transfer between different species has also been reported to contribute to the spread of resistance to antimicrobials, for example penicillin [4] and sulphonamides [5]. The hypothesis put forward [2] was that the sulphonamide resistance of N. meningitidis originated from a commensal Neisseria