SULFONAMIDE RESISTANCE IN STREPTOCOCCUS-PYOGENES IS ASSOCIATED WITH DIFFERENCES IN THE AMINO-ACID-SEQUENCE OF ITS CHROMOSOMAL DIHYDROPTEROATE SYNTHASE

Sulfonamide resistance in recent isolates of Streptococcus pyogenes wa s found to be associated with alterations of the chromosomally encoded dihydropteroate synthase (DHPS). There were 111 different nucleotides (13.8%) in the genes found in susceptible and resistant isolates, res pectively, resulting in 30 amino acid changes (11.3%), These substanti al changes suggested the possibility of a foreign origin of the resist ance gene, in parallel to what has already been found for sulfonamide resistance in Neisseria meningitidis. The gene encoding DHPS was linke d to at least three other genes encoding enzymes of the folate pathway , These genes mere in the order GTP cyclohydrolase, dihydropteroate sy nthase, dihydroneopterin aldolase, and hydroxymethyldihydropterin pyro phosphokinase, The nucleotide differences in genes from resistant and susceptible strains extended from the beginning of the GTP cyclohydrol ase gene to the end of the gene encoding DHPS, an additional indicatio n for gene transfer in the development of resistance. Kinetic measurem ents established different affinities for sulfathiazole for DHPS enzym es isolated from resistant and susceptible strains.