1887

Abstract

Sulphonamide resistance in some clinical isolates of is associated with an insertion in the chromosomal gene leading to the addition of two amino acids, serine and glycine, in the drug target enzyme dihydropteroate synthase (DHPS). Removal of the insertion resulted in a markedly higher for the substrate -aminobenzoic acid and a markedly lower for 2-amino-4-hydroxy-6-(hydroxymethyl)-7,8-dihydropteridine pyrophosphate. In the same isolates an additional important difference, compared to wild-type enzymes, was found at amino acid position 68, which is a proline in most DHPS enzymes, but is serine in one and leucine in another clinical isolate of sulphonamide-resistant . The alteration at position 68 was found to affect mainly the level of sulphonamide resistance and had only a minor effect on the for the substrates. Introduction of the serine-glycine dipeptide at position 194 and a proline to serine substitution at position 68 in DHPS from normal, susceptible failed to produce a functional sulphonamide-resistant enzyme. The conclusion of this study is that it is not possibile to change a normal chromosomally encoded DHPS of to a sulphonamide-resistant one simply by an insertion of serine and glycine as seen in clinical isolates. It is likely that the resistance gene found in clinical isolates has evolved in another bacterial species where a combination of other amino acid changes may have contributed to produce a functionally resistant enzyme. This new resistance gene may have then been introduced into by natural transformation.

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2000-05-01
2020-04-04
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