We now provide a detailed characterization of sulfonamide resistance in Neisseria meningitidis. It includes kinetic characteristics of those resistance variations of dihydropteroate synthase observed in clinical isolates of resistant pathogens, studied with site-directed mutagenesis. It is meant as an illustration at the molecular level of what has happened to a cheap and efficient antibacterial agent under the evolution of resistance.

After sulfonamides were introduced for clinical use in the 1930s, they were frequently used in both prophylaxis and treatment of infectious meningitis, a disease which without treatment shows a very high mortality. The etiological agent, N. meningitidis, soon developed sulfonamide resistance. This and the emergence of other more efficient agents has meant that sulfonamides have not been used for this disease for decades, which ought to mean that sulfonamide-resistant isolates of N. meningitidis should not exist today according to the argument described earlier for mutational sulfonamide resistance. They do, however, and are in fact common among present-day isolates of this pathogen. This means that they have not been selected away in the absence of sulfonamides. This in turn means that sulfonamide resistance has not hindered the resistant strains in their growth competition with their susceptible relatives. The fitness cost of resistance assumed must have been compensated in some way. The resistance remaining today can be looked at as a scar left by an earlier antibacterial treatment frequently used. It is an illustration of how our use of antibacterial agents changes bacterial evolution.

A closer study of the sulfonamide resistance mechanism among meningococci revealed surprisingly large differences between resistant and susceptible isolates in the gene expressing dihydropteroate synthase, the target enzyme of sulfonamides. Nucleotide sequence determinations of the folP gene, as it is called, from many susceptible and resistant isolates showed that there are two classes of resistance genes. In one of these the resistance folP gene differed by 10% in its sequence from that of susceptible isolates. This very large difference cannot be due to mutations accrued over time but must reflect a horizontal transfer of folP DNA between bacteria. This could be understood as spontaneous transformation, since Neisseria bacteria have the ability to take up DNA from relatives and incorporate it in their genomes. This ability gives Neisseria bacteria access to a common stock of genes that is much larger than that of the single species. Among the sulfonamide-resistant strains there were also folP genes showing a mosaic of sorts, where only the central part corresponded to the resistance gene, while the outer parts were identical to those of a susceptible folP (Fig. 1).

Fig1. Sulfonamide resistance in N. meningitidis. Comparisons of the nucleotide sequences of folP genes from different sulfonamide resistant and sulfonamide-susceptible clinical isolates of N. meningitidis. The sequence differences in the stylized gene representations are denoted by differently marked areas and percentages. Sur, the resistance gene; Sus, the susceptibility gene. The six extra nucleotides mentioned in the text are located at the triangle symbol.

Other Neisseria species are most likely to be the origin of the resistance gene. In these species, sulfonamide-resistant dihydropteroate synthases could be occurring naturally; that is, they could have evolved structurally as not being able to bind sulfonamides. There is a parallel to this in plasmid-borne genes for sulfonamide resistance, described later in the chapter. As an alternative, the sulfonamide resistance could have developed in harmless commensals and later, transferred into pathogenic Neisseria bacteria (this is developed a little bit more later). The idea of horizontal transfer of resistance-mediating DNA is supported by the observation of an 80-base pair DNA fragment from the corresponding part of folP in N. gonorrhoeae showing a 20% sequence difference from N. meningitidis and located in a sulfonamide susceptible strain of N. meningitidis. This is an illustration of the horizontal mobility of genetic material between related Neis seria species. This mosaic formation in Neisseria is shown in Figure 2.

Fig2. Transformation of sulfonamide resistance into N. meningitidis. Schematic illustration of the horizontal transfer of genetic material between Neisseria species, which after recombination gives rise to sulfonamide resistance ; dhps, dihydropteroate synthase; Sur, sulfonamide resistant; Sus, sulfonamide susceptible.

It could be added, speculatively, that the horizontal mobility described must be regulated in some way lest the species identity be jeopardized. On the other hand, it could be suggested that the selection pressure of our antibiotics is so strong that it could force itself through this regulation and, in the long run, influence the species barriers between pathogenic bacteria. The sulfonamide resistance gene in N. meningitidis described earlier has one additional characteristic. It has six extra nucleotides inserted at one point in its sequence, corresponding to two extra amino acids, glycine and serine, in the dihydropteroate synthase expressed (Fig. 1). If these two amino acids are removed experimentally by site-directed mutagenesis, the dihydropteroate synthase expressed becomes sulfonamide susceptible, implying that they are decisive for resistance. In the experimental system for this determination the folP gene has been moved from the Neisseria chromosome to a small plasmid, which in turn was introduced in an experimental bacterium. In a test tube system such as that, the folP DNA can be taken out, manipulated by site-directed mutagenesis, and inserted in an experimental bacterium whose sulfonamide susceptibility can then be determined.

The other class of sulfonamide-resistant N. meningitidis show a5%difference in their folP nucleotide sequence compared to that of a susceptible strain, and also lack the two extra amino acids, serine and glycine, in their expressed dihydropteroate synthase. Several of these resistance genes are identical between different resistant bacterial isolates but different from that of a susceptible isolate. This again implies a horizontal spread of resistance, in this case of the entire target enzyme gene (Fig.1).

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