Resistance to Sulfonamide
المؤلف:
Ola Sköld, M.D., Ph.D
المصدر:
Antibiotics and Antibiotic Resistance
الجزء والصفحة:
p34-35
2025-07-29
283
As mentioned, an early reason for the diminished use of sulfonamides was the rapid development of resistance in many pathogens: for example, streptococci, meningococci, and gonococci. Resistance toward sulfonamides is now also very common among gram-negative enterobacteria infecting the urinary tract. The molecular mechanisms of sulfonamide resistance differ markedly between different bacteria and have become investigated only in relatively recent years. The simplest mechanism includes mutational changes in the sulfonamide target enzyme dihydropteroate synthase (Fig. 1) that limit binding of the drug and thus mitigate the competition with the normal substrate p-aminobenzoic acid. Dihydropteroate synthase catalyzes the next-to-last step in the enzymic pathway leading to folic acid. In this step the pteridin nucleus of folic acid is linked to p-aminobenzoic acid. The structural similarity between sulfonamide and p-aminobenzoic acid and the high affinity of sulfonamide to the enzyme effects a competitive inhibition of dihydropteroate formation and, in turn, of folic acid formation. If a spontaneous mutation hits the chromosomal gene expressing dihydropteroate synthase, changing the enzyme structure such that it binds sulfonamide less tightly, the competition with p-aminobenzoic acid will be less pronounced, and its host then shows sulfonamide resistance. This phenomenon was shown in a simple laboratory experiment where E. coli bacteria were spread on agar plates containing inhibiting concentrations of sulfonamide. Single colonies, about one in 100 million of totally spread bacteria, showed resistance and grew out to colonies. The nucleotide sequence of the dihydropteroate synthase gene in those resistant bacteria showed that a spontaneous point mutation had occurred, exchanging one nucleotide and in turn exchanging one amino acid in the enzyme expressed.
Fig1. Point of action of sulfonamides on the folic acid synthesis of bacteria, the last two steps of which are shown schematically. The next-to-last step is catalyzed by the enzyme dihydropteroate synthase, which is the target of sulfonamides.
Closer studies of this resistance enzyme showed a 150-fold increase in the value of the inhibition constant (Ki). This means that the concentration of sulfonamide has to be increased150-fold compared to that needed for the same inhibition of the nonmutated enzyme. It could be seen, however, that the host bacterium had had to pay a price for its resistance, in that the mutationally changed enzyme needed a 10-fold higher concentration of its normal substrate, p-aminobenzoic acid, to function optimally (a 10-fold increase in the Km). The mutated enzyme also showed temperature sensitivity. The presence of sulfonamide creates an acute survival situation in which a mutationally changed enzyme is selected to help bacteria survive, but at the price of a less efficient enzyme differing from the optimal structures elected during the long evolution of bacteria. This would mean that bacteria reverting to their original susceptibility ought to be selected in the absence of sulfonamide. These arguments regarding molecular evolution and antibiotics resistance are very important for the medical assessment of resistance against antibacterial agents in health care: for example, the question of whether antibiotic resistance seen in clinical contexts incurs a fitness cost on the host bacterium, thus counter selecting against resistant bacteria in the absence of antibiotics.
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