Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

The antibacterial activity of p-aminobenzoic acid against Listeria monocytogenes, Salmonella enteritidis and Escherichia coli was compared with the activity of commonly used acidulants: formic, propionic, acetic, lactic and citric acids. Viable count evaluations and MIC determinations indicated that p-aminobenzoic acid caused greater inhibitory effects than the other organic acids. The activity of p-aminobenzoic acid on the growth of the test organisms at selected pH values indicated that p-aminobenzoic acid was more active at low pH than at high pH. Uptake studies showed that the uptake of p-aminobenzoic acid by E. coli was markedly decreased as the pH values increased. Electron micrographs of E. coli cells grown in the presence of p-aminobenzoic acid indicate that p-aminobenzoic acid caused marked damage to the cell envelope. It is suggested that p-aminobenzoic acid has at least two mechanisms of action: one mechanism in common with other organic acids and the other mechanism by interfering with the synthesis of the peptidoglycan layer by an action on the dihydrofolate reductase enzyme.
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PMID:Activity of p-aminobenzoic acid compared with other organic acids against selected bacteria. 773 Jan 99

There is accumulating evidence that sub-inhibitory concentrations (sub-MICs) of many antibiotics are not without effect on bacteria and even though they do not kill bacteria, they are still able to interfere with some important aspects of bacterial cell function. The aim of the present study was to investigate the effect of sub-MICs of brodimoprim and trimethoprim on Escherichia coli and Staphylococcus aureus adhesiveness to human mucosal cells. Sub-MICs of brodimoprim down to 1/32 MIC (0.03 microgram/ml) significantly reduced the E. coli adhesion to human buccal epithelial cells and this inhibition was significantly higher than the corresponding pattern for trimethoprim. Adhesion of S. aureus was significantly reduced down to 1/16 MIC for both brodimoprim and trimethoprim but no significant differences resulted between the two patterns. 2,4 Diaminopyrimidines and related structures have a high affinity for the enzyme dihydrofolate reductase and this causes a reduction in the synthesis of essential purines, thus reducing also DNA and the synthesis or expression of surface adhesins.
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PMID:Inhibition of bacterial adhesion by sub-inhibitory concentrations: brodimoprim vs trimethoprim. 819 36

Trimethoprim resistance in 64 Escherichia coli urinary isolates from five hospitals in Greece was studied. Of the 40 isolates exhibiting transferable high-level resistance (MIC > 1024 mg/L), 21 hybridized with a specific probe for dihydrofolate reductase (DHFR) I, 13 with a probe for DHFR II, and one with a probe for DHFR V. Eleven isolates hybridized with a probe for transposon Tn7. Among the 17 isolates with non-transferable high-level resistance, seven hybridized with the probe for DHFR I, three with the probe for DHFR II, and eight were Tn7-positive. None of the seven isolates with low-level resistance (MIC 4-1024 mg/L) reacted with the probes used. Of the 28 isolates positive for DHFR I, 12 (43%) failed to hybridize with the Tn7 probe. Conversely, three isolates hybridized with the Tn7 probe, but not with the probe for DHFR I. Colony hybridization experiments showed that all but three transconjugants reacted similarly to their respective parent strains. The plasmids coding for trimethoprim-resistant DHFRs were found to differ on the basis of restriction enzyme analysis. These findings suggest that trimethoprim resistance among E. coli urinary isolates in Greece is mediated predominantly by heterogeneous transferable plasmids encoding either DHFR I or DHFR II. The dissociation between DHFR I and Tn7, together with the high incidence of trimethoprim-resistant isolates which did not hybridize with the probes for the common DHFR I or II types, indicates the continued evolution of trimethoprim resistance determinants.
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PMID:Prevalence of the type I and type II DHFR genes in trimethoprim-resistant urinary isolates of Escherichia coli from Greece. 839 96

WR99210, a dihydrofolate reductase inhibitor, has promising in vitro activity against Mycobacterium avium complex (MAC). The in vitro activities of WR99210 alone and in combination with a fixed concentration of dapsone (0.5 microgram/ml) were evaluated against 35 clinical MAC isolates by a broth dilution method. The MIC at which 50% of isolates were inhibited (MIC50) and MIC90 of WR99210 alone were 2 and 8 micrograms/ml, respectively. The MIC50 and MIC90 of WR99210 in combination with dapsone were 0.25 and 4 micrograms/ml, respectively. Overall, 75% of the MAC isolates displayed enhanced susceptibility to the combination.
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PMID:Enhanced in vitro activity of WR99210 in combination with dapsone against Mycobacterium avium complex. 891 80

The sequence of the trimethoprim resistance gene of the 3.7-kb plasmid (pIP823) that confers high-level resistance (MIC, 1,024 microg/ml) to Listeria monocytogenes BM4293 was determined. The gene was identical to dfrD recently detected in Staphylococcus haemolyticus MUR313. The corresponding protein, S2DHFR, represents the second class of high-level trimethoprim-resistant dihydrofolate reductase identified in gram-positive bacteria. We propose that trimethoprim resistance in L. monocytogenes BM4293 could originate in staphylococci.
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PMID:Emergence of the trimethoprim resistance gene dfrD in Listeria monocytogenes BM4293. 914 82

Antimicrobial resistance patterns of Salmonella serotype Typhimurium isolates obtained during the period 1987-1994 were examined and the molecular epidemiology and the mechanisms of resistance to ampicillin, chloramphenicol and trimethoprim were investigated in 24 strains isolated during 1994. Resistance to ampicillin increased from 18% to 78%, to chloramphenicol from 15% to 78%, to tetracycline from 53% to 89% and to co-trimoxazole from 3% to 37%, whereas resistance to norfloxacin remained at 0%. Of Salmonella serotype Typhimurium strains isolated during 1994, all ampicillin-resistant strains had an MIC > 256 mg/L, except one strain in which the MIC was 64 mg/L. Twelve strains (52%) had a TEM-type beta-lactamase, nine (39%) a CARB-type beta-lactamase and two strains (8%) had an OXA-type beta-lactamase. Chloramphenicol acetyl-transferase activity was detected in only nine (47%) of 19 chloramphenicol resistant strains, whereas all eight trimethoprim-resistant strains produced a dihydrofolate reductase type Ia enzyme. Three different epidemiological groups were defined by either low-frequency restriction analysis of chromosomal DNA and pulsed-field gel electrophoresis or repetitive extragenic palindromic-PCR. The latter technique provided an alternative, rapid and powerful genotyping method for S. Typhimurium. Although quinolones provide a good therapeutic alternative, the multiresistance of S. Typhimurium is of public health concern and it is important to continue surveillance of resistance levels and their mechanisms.
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PMID:Increase in incidence of resistance to ampicillin, chloramphenicol and trimethoprim in clinical isolates of Salmonella serotype Typhimurium with investigation of molecular epidemiology and mechanisms of resistance. 1050 79

The in vitro activities of iclaprim, a novel dihydrofolate reductase inhibitor, azithromycin, and levofloxacin were tested against 10 strains of Chlamydia trachomatis and 10 isolates of Chlamydia pneumoniae. For C. trachomatis and C. pneumoniae, the iclaprim MIC and minimal bactericidal concentration at which 90% of isolates were inhibited (MIC(90) and MBC(90)) were 0.5 micro g/ml, compared to an azithromycin MIC(90) and MBC(90) of 0.125 micro g/ml and levofloxacin MIC(90)s and MBC(90)s of 1 micro g/ml for C. trachomatis and 0.5 micro g/ml for C. pneumoniae.
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PMID:In vitro activity of a novel diaminopyrimidine compound, iclaprim, against Chlamydia trachomatis and C. pneumoniae. 1510 51

Bacillus anthracis is reported to be naturally resistant to trimethoprim (TMP), a drug that inhibits dihydrofolate reductase (DHFR), a key enzyme in the folate pathway. A microdilution broth assay established that the MIC of TMP for B. anthracis Sterne is >2,048 but < or =4,096 microg/ml. A putative DHFR sequence was amplified from B. anthracis Sterne genomic DNA. The PCR product was cloned into the Invitrogen pCRT7/CT-TOPO vector, followed by transformation into Escherichia coli TOP10F' chemically competent cells. Plasmid DNA from a clone showing the correct construct with a thrombin cleavage site attached downstream from the terminus of the cloned PCR product was transformed into E. coli BL21 Star (DE3)pLysS competent cells for expression of the six-histidine-tagged fusion protein and purification on a His-Bind resin column. Functionality of the purified Sterne recombinant DHFR (Sterne rDHFR) was confirmed in an established enzyme assay. The 50% inhibitory concentrations of TMP and methotrexate for the Sterne rDHFR were found to be 77,233 and 12.2 nM, respectively. TMP resistance was observed with E. coli BL21 Star (DE3)pLysS competent cells transformed with the Sterne DHFR gene. Alignment of the amino acid sequence of the Sterne DHFR gene revealed 100% homology with various virulent strains of B. anthracis. These results confirm the natural resistance of B. anthracis to TMP and clarify that the resistance is correlated to a lack of selectivity for the chromosomally encoded gene product. These findings will assist in the development of narrow-spectrum antimicrobial agents for treatment of anthrax.
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PMID:Functional cloning of Bacillus anthracis dihydrofolate reductase and confirmation of natural resistance to trimethoprim. 1556 38

The catechin epigallocatechin gallate, one of the main constituents of green tea, showed strong antibiotic activity against 18 isolates of Stenotrophomonas maltophilia (MIC range, 4 to 256 microg/ml). In elucidating its mechanism of action, we have shown that epigallocatechin gallate is an efficient inhibitor of S. maltophilia dihydrofolate reductase, a strategic enzyme that is considered an attractive target for the development of antibacterial agents. The inhibition of S. maltophilia dihydrofolate reductase by this tea compound was studied and compared with the mechanism of a nonclassical antifolate compound, trimethoprim. Investigation of dihydrofolate reductase was undertaken with both a trimethoprim-susceptible S. maltophilia isolate and an isolate with a high level of resistance. The enzymes were purified using ammonium sulfate precipitation, gel filtration, and methotrexate affinity chromatography. The two isolates showed similar levels of dihydrofolate reductase expression and similar substrate kinetics. However, the dihydrofolate reductase from the trimethoprim-resistant isolate demonstrated decreased susceptibility to inhibition by trimethoprim and epigallocatechin gallate. As with other antifolates, the action of epigallocatechin gallate was synergistic with that of sulfamethoxazole, a drug that blocks folic acid metabolism in bacteria, and the inhibition of bacterial growth was attenuated by including leucovorin in the growth medium. We conclude that the mechanism of action of epigallocatechin gallate on S. maltophilia is related to its antifolate activity.
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PMID:Antifolate activity of epigallocatechin gallate against Stenotrophomonas maltophilia. 1598 Mar 68

New and improved therapeutics are needed for Bacillus anthracis, the etiological agent of anthrax. To date, antimicrobial agents have not been developed against the well-validated target dihydrofolate reductase (DHFR). In order to address whether DHFR inhibitors could have potential use as clinical agents against Bacillus, 27 compounds were screened against this enzyme from Bacillus cereus, which is identical to the enzyme from B. anthracis at the active site. Several 2,4-diamino-5-deazapteridine compounds exhibit submicromolar 50% inhibitory concentrations (IC(50)s). Four of the inhibitors displaying potency in vitro were tested in vivo and showed a marked growth inhibition of B. cereus; the most potent of these has MIC(50) and minimum bactericidal concentrations at which 50% are killed of 1.6 mug/ml and 0.09 mug/ml, respectively. In order to illustrate structure-activity relationships for the classes of inhibitors tested, each of the 27 inhibitors was docked into homology models of the B. cereus and B. anthracis DHFR proteins, allowing the development of a rationale for the inhibition profiles. A combination of favorable interactions with the diaminopyrimidine and substituted phenyl rings explains the low IC(50) values of potent inhibitors; steric interactions explain higher IC(50) values. These experiments show that DHFR is a reasonable antimicrobial target for Bacillus anthracis and that there is a class of inhibitors that possess sufficient potency and antibacterial activity to suggest further development.
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PMID:Structure-activity relationships of Bacillus cereus and Bacillus anthracis dihydrofolate reductase: toward the identification of new potent drug leads. 1700 26


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