Dihydrofolate reductase from Neisseria sp - PubMed (original) (raw)
Dihydrofolate reductase from Neisseria sp
D R Averett et al. Antimicrob Agents Chemother. 1979 Mar.
Abstract
Members of the genus Neisseria are relatively nonsusceptible to trimethoprim, an inhibitor of dihydrofolate reductase. For example, the minimal inhibitory concentration (MIC) of trimethoprim for N. gonorrhoeae ranges from 2 to 70 mug/ml, whereas the MIC for Escherichia coli is 0.2 mug/ml or less. In an effort to understand this difference, dihydrofolate reductase was partially purified from five Neisseria species and compared with the enzyme from E. coli. N. gonorrhoeae dihydrofolate reductase was similar to that from E. coli in molecular weight (18,000) and affinity for the substrates reduced nicotinamide adenine dinucleotide phosphate and dihydrofolate (K(m) = 13 and 8 muM, respectively). However, the gonococcal enzyme had a decreased affinity for trimethoprim, with an apparent K(i) of 45 x 10(-9) M, some 30-fold greater than the E. coli value of 1.2 x 10(-9) M. These enzymes also differed in their isoelectric points and pH activity profiles. Within the genus Neisseria, the dihydrofolate reductase isolated from N. meningitidis and N. lactamica resembled the N. gonorrhoeae enzyme, and only small differences were detected for the N. flavescens and Branhamella catarrhalis dihydrofolate reductases. These data indicate that the relatively poor affinity of trimethoprim for the dihydrofolate reductase from these organisms may be largely responsible for the relative nonsusceptibility of Neisseria sp. to trimethoprim. The contribution of other resistance mechanisms to the overall nonsusceptibility was assessed. Strains of N. gonorrhoeae with altered cell envelope permeability had MIC values less than twofold different from those of isogenic wild-type strains. Also, a direct relationship was observed between the affinity of trimethoprim analogs for gonococcal dihydrofolate reductase and the MIC of these compounds for the gonococcus. These observations suggest that the cell envelope of N. gonorrhoeae is not impermeable to trimethoprim. Changes in the amount of dihydrofolate reductase activity could cause alterations in the susceptibility of the gonococcus to trimethoprim, as demonstrated with N. gonorrhoeae strains selected for trimethoprim resistance after chemical mutagenesis. However, the level of dihydrofolate reductase activity in wild-type N. gonorrhoeae was similar to that of E. coli, indicating that the difference in the susceptibility of these organisms is not due to greater amounts of enzyme in N. gonorrhoeae.
Similar articles
- Comparison of dihydrofolate reductases from trimethoprim- and sulfonamide-resistant strains of Neisseria gonorrhoeae.
Ho RI, Lai PH, Corman L, Ho J, Morse SA. Ho RI, et al. Sex Transm Dis. 1978 Apr-Jun;5(2):43-50. doi: 10.1097/00007435-197804000-00002. Sex Transm Dis. 1978. PMID: 10328030 - Neisseriaceae, a group of bacteria with dihydrofolate reductases, moderately susceptible to trimethoprim.
Then RL. Then RL. Zentralbl Bakteriol Orig A. 1979 Dec;245(4):450-8. Zentralbl Bakteriol Orig A. 1979. PMID: 44939 - Site-directed mutagenesis of mouse dihydrofolate reductase. Mutants with increased resistance to methotrexate and trimethoprim.
Thillet J, Absil J, Stone SR, Pictet R. Thillet J, et al. J Biol Chem. 1988 Sep 5;263(25):12500-8. J Biol Chem. 1988. PMID: 3045118 - Trimethoprim and brodimoprim resistance of gram-positive and gram-negative bacteria.
Thomson CJ. Thomson CJ. J Chemother. 1993 Dec;5(6):458-64. J Chemother. 1993. PMID: 8195838 Review. - Trimethoprim and other nonclassical antifolates an excellent template for searching modifications of dihydrofolate reductase enzyme inhibitors.
Wróbel A, Arciszewska K, Maliszewski D, Drozdowska D. Wróbel A, et al. J Antibiot (Tokyo). 2020 Jan;73(1):5-27. doi: 10.1038/s41429-019-0240-6. Epub 2019 Oct 2. J Antibiot (Tokyo). 2020. PMID: 31578455 Free PMC article. Review.
Cited by
- Safety Aspects and Rational Use of Single Intramuscular Dose Ceftriaxone: Clinical Insights on the Management of Uncomplicated Gonococcal Infections.
Allen GP, Morrill HL. Allen GP, et al. Drug Healthc Patient Saf. 2023 Nov 3;15:159-170. doi: 10.2147/DHPS.S350763. eCollection 2023. Drug Healthc Patient Saf. 2023. PMID: 37941731 Free PMC article. Review. - Canary in the Coal Mine: How Resistance Surveillance in Commensals Could Help Curb the Spread of AMR in Pathogenic Neisseria.
Goytia M, Wadsworth CB. Goytia M, et al. mBio. 2022 Oct 26;13(5):e0199122. doi: 10.1128/mbio.01991-22. Epub 2022 Sep 26. mBio. 2022. PMID: 36154280 Free PMC article. Review. - Antimicrobial resistance in Neisseria gonorrhoeae: history, molecular mechanisms and epidemiological aspects of an emerging global threat.
Costa-Lourenço APRD, Barros Dos Santos KT, Moreira BM, Fracalanzza SEL, Bonelli RR. Costa-Lourenço APRD, et al. Braz J Microbiol. 2017 Oct-Dec;48(4):617-628. doi: 10.1016/j.bjm.2017.06.001. Epub 2017 Jul 12. Braz J Microbiol. 2017. PMID: 28754299 Free PMC article. Review. - Branhamella catarrhalis: an organism gaining respect as a pathogen.
Catlin BW. Catlin BW. Clin Microbiol Rev. 1990 Oct;3(4):293-320. doi: 10.1128/CMR.3.4.293. Clin Microbiol Rev. 1990. PMID: 2121328 Free PMC article. Review.
References
- J Biol Chem. 1957 Oct;228(2):1031-8 - PubMed
- J Gen Microbiol. 1961 Oct;26:303-12 - PubMed
- J Bacteriol. 1963 Jun;85:1274-9 - PubMed
- J Med Pharm Chem. 1962 Nov;91:1103-23 - PubMed
- J Antimicrob Chemother. 1977 May;3(3):197-8 - PubMed
MeSH terms
Substances
LinkOut - more resources
Full Text Sources