Genetic basis of the association of sulphonamide resistance with methionine auxotrophy in Neisseria gonorrhoeae.

Selection by sulphonamides was investigated in Neisseria gonorrhoeae because a sulphonamide-resistant (Sulr), methionine-requiring (Met-) phenotype that was common in the era of sulphonamide therapy became rare in the penicillin era. Cultures of wild-type (SulsMet+) gonococci on a conventional medium containing sulphadiazine (2-10 micrograms ml-1) yielded numerous, nonidentical mutations of two met genes. The requirement of MetI- mutants was satisfied only by methionine, whereas MetII- mutants utilized either homocysteine or methionine. My theory that increased resistance to sulphonamides is a pleiotropic effect of methionine auxotrophy was confirmed by the return of sulphonamide susceptibility in all Met+ spontaneous mutants. Furthermore, the SulrMet- traits were introduced or eliminated together by DNA-mediated transformation. Sulphonamides are known to inhibit dihydropteroate synthase; consequently, they interrupt the entire sequence of reactions in the folate pathway including the methyl group transfer from N5-methyltetrahydrofolate to homocysteine to form methionine. The increased sulphonamide resistance of these Met- mutants is discussed in terms of conservation of the pool of essential tetrahydrofolate derivatives. The ease with which spontaneous forward and reverse met mutations can be obtained is unique among gonococcal genes.