Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.5.1.3 (dihydrofolate reductase)
 5,819 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Between July 1987 and June 1989, 1054 urinary isolates of enterobacteria from Kaohsiung, Taiwan were studied for their trimethoprim resistance. Trimethoprim resistance was defined as MIC greater than 4 micrograms/ml and high-level resistance by MIC greater than 1000 micrograms/ml. The incidence of trimethoprim resistance increased from 33.6% in 1987 to 42.1% in 1989. Among the resistant strains studied, 90% were resistant to high levels of trimethoprim. An increase in the proportion of resistant strains (33.9-46.3%) exhibiting high-level non-transferable trimethoprim resistance was noted. The distribution of the dihydrofolate reductase (DHFR) genes by colony hybridization in 374 trimethoprim-resistant isolates revealed the presence of type I and type V DHFR genes in most of these isolates (45.4% and 10.4% respectively). Type I was predominant in Escherichia coli whereas type V was frequently seen in Enterobacter spp. None showed homology with the type II and type III DHFR probe DNA. In addition, transposon Tn7 was present in 7.8% of 374 trimethoprim-resistant enterobacteria.
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PMID:The distribution of the DHFR genes in trimethoprim-resistant urinary tract isolates from Taiwan. 133 41

In 1990 an increased number of strains of Shigella boydii serotype 2 were isolated from different regions of Bulgaria. Strains were reported as sporadic, although they showed identical phenotypic characteristics, including resistance to ampicillin, carbenicillin, streptomycin, sulfonamide, tetracycline, ticarcillin, and trimethoprim. The objective of this study was to determine the genetic relatedness of the strains and the mechanism of their antimicrobial resistance. Plasmid fingerprinting showed an identical pattern for 23 of 25 of the selected strains. All 25 strains tested transferred their resistances en bloc to an Escherichia coli recipient. Transconjugants contained a 112-kb R plasmid which carried all the resistance genes, including that conferring type I dihydrofolate reductase-mediated trimethoprim resistance (MIC greater than 2,000 micrograms/ml). Riboprobe analysis showed identical restriction length fragment polymorphisms, suggesting a highly conserved genome. All findings indicate that strains of S. boydii serotype 2 isolated in 1990 from different regions of Bulgaria were highly related genetically and can be considered representatives of a single bacterial clone. The presence of an R plasmid and selection pressure because of the usage of antimicrobial agents, particularly trimethoprim, have likely facilitated the spread of the clone throughout the country.
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PMID:Molecular epidemiology of trimethoprim-resistant Shigella boydii serotype 2 strains from Bulgaria. 162 59

Aditoprim, a broad spectrum antimicrobial agent acting as a reversible dihydrofolate reductase inhibitor, was intravenously injected into four 12 to 24-year old horses at a dosage of 5 mg/kg b. w. Blood samples were collected over a 48-hour period after drug injection, and the separated plasma samples were assayed for aditoprim by high performance liquid chromatography. The body temperature, heart rate, respiration rate, and behaviour were recorded during the experiment. The bilirubin and urea concentrations were also determined in several plasma samples, and liver function tests were carried out. The concentrations of aditoprim in the plasma of horses were higher than the MIC of this drug against recently isolated pathogens for 6-13 h (Pasteurella haemolytica A 1) to 48 h (E. coli). The main pharmacokinetic characteristics of aditoprim in horses were: a large volume of distribution, reaching a mean value of 7.8 l/kg; a mean plasma clearance of 5.0 l/min; a plasma elimination half-life of 12 h. The clinical observations, blood chemistry, and liver function tests all demonstrated that the drug was well tolerated by the horses, although it was injected intravenously as a 25% solution. It was concluded that the 25% aditoprim injection solution could be used in horses without adverse effects at 5 mg/kg. Furthermore, aditoprim should demonstrate good antibacterial effects in horses when intravenously injected once a day.
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PMID:Plasma disposition and tolerance of aditoprim in horses after single intravenous injection. 211 4

Trimethoprim (TMP), either alone or in combination with sulphonamides, is commonly used for treating urinary tract infections. In Finland, TMP alone has been in clinical use since 1973. TMP resistance in the major outpatient urinary tract pathogen, Escherichia coli, increased during 1978-1988 from 5% to 16% in the Turku area, during 1980-1988 from 3% to 19% in the Helsinki area and also during 1980-1988 from 3% to 14% in the Rovaniemi area. The majority (91%) of TMP-resistant strains were highly-resistant to TMP (MIC greater than or equal to 1024 mg/l). The most common (57%) TMP resistance gene, detected by DNA hybridization, was the type I dihydrofolate (DHFR) gene. The type II DHFR genes were found in less than 3% of the strains studied. No positive hybridizations were detected with the type III DHFR probe, and only a few positive hybridizations were found with the type V DHFR probe. Forty percent of the isolates did not hybridize with any of the DHFR probes used, suggesting additional unknown resistance mechanisms responsible for the high-level TMP resistance. These unknown TMP resistance mechanisms, together with the type I DHFR-mediated resistance, were responsible for the increase of TMP resistance among the E. coli strains studied.
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PMID:The emergence and mechanisms of trimethoprim resistance in Escherichia coli isolated from outpatients in Finland. 218 60

The new in vitro screening system reported earlier was adopted to determine anti-M. leprae activity of a dihydrofolate reductase inhibitor, brodimoprim, and the results were compared with those obtained using mouse foot-pad technique. Even though the MIC of brodimoprim against M. leprae was very high compared to other commonly used anti-leprosy drugs, in combination with dapsone it showed a remarkable synergistic activity in inhibiting the growth of M. leprae at concentrations much lower than the MICs of each of the drugs used singly. Similar effects were also demonstrated in mouse foot-pad experiments.
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PMID:Effect of brodimoprim on Mycobacterium leprae in vitro and in mouse foot-pads. 219 64

The frequency of trimethoprim resistance among Escherichia coli isolates from urine samples collected at Turku City Hospital, Turku, Finland, remained at 40% during 1984 to 1988. The proportion of highly resistant (MIC, greater than or equal to 1,024 micrograms/ml) isolates increased, however, and most of these harbored the type I dihydrofolate reductase gene. Only a few isolates possessed type II or VII genes.
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PMID:Trimethoprim resistance in Escherichia coli isolates from a geriatric unit. 229 68

Bacterial dysentery due to Shigella sonnei remains a serious public health problem in developed countries, including Bulgaria. At the National Shigella Reference Laboratory in Sofia, 17,126 strains of S. sonnei from epidemics and sporadic cases collected from 1973 to 1987 were studied. Antibiotic susceptibility testing, phage typing, colicin typing, and biotyping were performed for all strains to allow intraspecies differentiation and to track any clonal distribution. Of all strains, 84.3% were resistant to one or more antimicrobials, the most frequent being tetracycline (Tet), streptomycin (Str), sulfonamide (Sul), chloramphenicol (Chl), ampicillin (Amp), and trimethoprim (Tmp). Resistance patterns most prevalent for successive 5-y periods included Tet, StrSulTet, and AmpChlStrSulTet, respectively. For the final 5 y, a new pattern (AmpKanStrSulTetTm [Kan = kanamycin]) was spread throughout the country by two trimethoprim-resistant clones. High-level resistance to trimethoprim (MIC greater than 1500 micrograms/mL) in both clones was determined by dihydrofolate reductase type I. The genes for trimethoprim resistance were located on a conjugative R-plasmid of approximately 145 kilobases which cotransferred all other antimicrobial resistances. A similar-sized R-plasmid had been found in earlier isolates of Bulgarian S. sonnei, suggesting that new antimicrobial resistance genes had been sequentially added to an ancestral R-plasmid. Controlling the expression of these new as well as older antimicrobial resistances, particularly for enteric pathogens, must involve reduction in usage of generic antimicrobial agents.
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PMID:Dissemination of trimethoprim-resistant clones of Shigella sonnei in Bulgaria. 264 61

Trimethoprim resistance was investigated in cystic fibrosis isolates of Pseudomonas cepacia. Determination of the MIC of trimethoprim for 111 strains revealed at least two populations of resistant organisms, suggesting the presence of more than one mechanism of resistance. Investigation of the antibiotic target, dihydrofolate reductase, was undertaken in both a susceptible strain and a strain with high-level resistance (MIC, greater than 1,000 micrograms/ml). The enzyme was purified by using ammonium sulfate precipitation, gel filtration, and ion-exchange chromatography. Specific activities, molecular weights, isoelectric points, and substrate kinetics were similar for both enzymes. However, the dihydrofolate reductase from the trimethoprim-resistant strain demonstrated decreased susceptibility to inhibition by trimethoprim and increased susceptibility to inhibition by methotrexate, suggesting that these two enzymes are not identical. We conclude that the mechanism of trimethoprim resistance in this strain with high-level resistance is production of a trimethoprim-resistant dihydrofolate reductase.
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PMID:Isolation and characterization of dihydrofolate reductase from trimethoprim-susceptible and trimethoprim-resistant Pseudomonas cepacia. 280 52

Resistance to trimethoprim (Tp) is mediated by a plasmid-encoded gene in staphylococci. The gene is responsible for high-level resistance (MIC, greater than 1,000 micrograms/ml) in both its native host and when cloned on high-copy-number vectors in Escherichia coli. Analysis of subclones of the staphylococcal Tp gene on E. coli expression vectors and estimation of the size of full and truncated proteins produced in E. coli minicells generated an approximate size limit of 505 base pairs for the gene and 18,500 daltons for the gene product. Crude extracts of E. coli containing the cloned gene had dihydrofolate reductase (DHFR) specific activity that was more than 100 times greater than that of control cells and more than 1,000 times more resistant to trimethoprim inhibition. The amount of trimethoprim required for a 50% reduction in the specific activity of staphylococcal DHFR differed from those of cells containing DHFR types I, II, or III, enzymes mediating Tp in members of the family Enterobacteriaceae. In addition, the size of the monomeric staphylococcal DHFR protein was larger than that of any of the gram-negative DHFRs both compared with published sequence data and as observed by direct comparison on polyacrylamide gels. Finally, there was no homology between a DNA fragment containing the cloned staphylococcal gene and DNA encoding any of the gram-negative DHFRs. Thus, the staphylococcal Tp gene codes for a single protein with DHFR activity that appears to be unrelated to DHFR genes that mediate Tp in members of the Enterobacteriaceae.
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PMID:Characterization of a staphylococcal trimethoprim resistance gene and its product. 282 86

In order to gain an insight into the distribution of resistance genes in Vibrio cholerae, we studied twenty-nine strains isolated from patients in Africa. Resistance to antibiotics in all strains except one was encoded by self-transferable plasmids belonging to incompatibility group Inc6-C. Tetracycline and chloramphenicol were poorly expressed in the original hosts but were easily detectable in the Escherichia coli transconjugants. Streptomycin resistance was due to synthesis of a 3"- or 6-aminoglycoside phosphotransferase. Based on MIC and hybridization data, high-level resistance to trimethoprim and O/129 was secondary to the presence of a dihydrofolate reductase of a new type, distantly related to type I activity. Our results confirm the presence in V. cholerae of beta-lactamases other than Tem-1.
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PMID:Genetic, biochemical and molecular characterization of strains of Vibrio cholerae multiresistant to antibiotics. 326 Jan 5


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