Evolution of the phenomenon of drug-resistance. II. Studies of the extracellular and intracellular derivatives of folic acid in relation to resistance to sulphathiazole and growth factor requirements

1960 ◽  
Vol 153 (951) ◽  
pp. 205-219 ◽  
Keyword(s):  
Folic Acid ◽  
Growth Factor ◽  
Resistant Strain ◽  
Sensitive Strain ◽  
Vitamin B ◽  
Intracellular Accumulation ◽  
E Coli ◽  
Dependent Strain ◽  
Resistant Strains ◽  
Derivatives Of

This study is a continuation of the results published previously (Sevag & Ishii 1958). It surveys quantitatively the extracellular and intracellular accumulation of p -aminobenzoic acid (PAB), pteridine, folic acid (FA) and citrovorum factor (CF) of the various sulphathiazole (ST)-sensitive and ST-resistant strains of Escherichia coli grown with and without ST. The altered enzymic activities of the resistant strain with respect to growth factor requirement is also determined. The following observations are made. The utilization of the exogenous PAB by the PAB-dependent strain is followed by the multiplication of cells. These events are followed by the extracellular accumulation of FA first and then CF. This pattern applies to other strains of E. coli and is in accordance with the well-known sequence of steps involved in the synthesis of PAB, pteridine, FA, CF and growth. It is shown that PAB accumulates principally extracellularly, and pteridine principally intracellularly. The synthesis of FA by the resistant strain is at least tenfold more resistant to ST than in the sensitive strain. In the resistant strain there is a greater intracellular than extracellular accumulation of FA and CF. In the sensitive strain this relationship is reversed. The resistant strains are inheritably capable of synthesizing greater amounts of pteridine, FA and CF. The PAB-dependent ST-sensitive strain can utilize a combination of 1-methionine and any of the purines, of 1-methionine alone, or vitamin B 12 alone in place of PAB for a partial or full growth. The related resistant strain, on the other hand, is unable to multiply in the salts-glucose medium with and without PAB. It requires a combination of 1-methionine and glycine for growth which cannot be replaced by any of the factors mentioned above. This requirement of the resistant strain for growth is analyzed as a deficiency of the enzymic transmethylations and transhydroxymethylation involving the function of CF in the resistant strain.

scholarly journals Activation of complement by serum-resistant Neisseria gonorrhoeae. Assembly of the membrane attack complex without subsequent cell death.

1982 ◽  
Vol 156 (4) ◽  
pp. 1235-1249 ◽  
Author(s):  
G R Harriman ◽  
E R Podack ◽  
A I Braude ◽  
L C Corbeil ◽  
A F Esser ◽  
...  
Keyword(s):  
Neisseria Gonorrhoeae ◽  
Resistant Strain ◽  
Membrane Attack Complex ◽  
Electron Microscopic Examination ◽  
Sensitive Strain ◽  
Binding Assays ◽  
Electron Microscopic ◽  
Dose Dependent Fashion ◽  
Normal Human ◽  
Resistant Strains

Interaction of the human complement system in normal human serum (NHS) with serum-resistant and -sensitive Neisseria gonorrhoeae was evaluated to better understand the mechanism of serum-resistance. Complement activity (CH50) was depleted from NHS in a dose-dependent fashion by both serum-resistant and -sensitive N. gonorrhoeae. No detectable CH50 remained in NHS incubated with 10(9) colony-forming units (CFU)/ml serum of either resistant or sensitive strains. When smaller numbers of bacteria were incubated with NHS, lesser, yet comparable, amounts of CH50 were depleted by both resistant and sensitive strains. Hemolytic C2 activity was diminished by 33% in the case of resistant N. gonorrhoeae (10(8) CFU/ml serum) and by 48% in the case of a sensitive strain. No detectable decreases in hemolytic C4 or C7 activities were found with either sensitive or resistant strains at this concentration. Both resistant and sensitive strains activated C1s in NHS. Resistant strains specifically activated 19-21% of radiolabeled C1s in NHS, whereas sensitive strains activated 18-32%. Both resistant and sensitive strains also activated C5 in NHS. In binding assays using radiolabeled C5 and C9 in NHS, resistant and sensitive strains bound comparable amounts of C5 and C9. The number of bound C5 and C9 molecules varied according to the number of bacteria or amount of serum used in the assay. The ratio of C9/C5 bound to a sensitive strain was 6.8, and to a resistant strain was 8.2, suggesting that C5 and C9 were incorporated into membrane attack complexes (MAC). Electron microscopic examination of resistant and sensitive strains incubated with NHS revealed that MAC is bound to the surfaces of the resistant strain as well as the sensitive strain.

Synthesis of 2-Deoxy-β-D-ribonucleosides and 2,3-Dideoxy-β-D-pentofuranosides on Immobilized Bacterial Cells

1994 ◽  
Vol 59 (10) ◽  
pp. 2303-2330 ◽  
Author(s):  
Ivan Votruba ◽  
Antonín Holý ◽  
Hana Dvořáková ◽  
Jaroslav Günter ◽  
Dana Hocková ◽  
...  
Keyword(s):  
The Other ◽  
Bacterial Cells ◽  
Amino Groups ◽  
E Coli ◽  
Pyrimidine Series ◽  
Acceptor Activity ◽  
Dependent Strain ◽  
Pyrimidine Bases ◽  
Heterocyclic Bases ◽  
Derivatives Of

Alginate gel-entrapped cells of auxotrophic thymine-dependent strain of E. coli catalyze the transfer of 2-deoxy-D-ribofuranosyl moiety of 2'-deoxyuridine to purine and pyrimidine bases as well as their aza and deaza analogs. All experiments invariably gave β-anomers; in most cases, the reaction was regiospecific, affording N9-isomers in the purine and N1-isomers in the pyrimidine series. Also a 2,3-dideoxynucleoside can serve as donor of the glycosyl moiety. The acceptor activity of purine bases depends only little on substitution, the only condition being the presence of N7-nitrogen atom. On the other hand, in the pyrimidine series the activity is limited to only a narrow choice of mostly short 5-alkyl and 5-halogeno uracil derivatives. Heterocyclic bases containing amino groups are deaminated; this can be avoided by conversion of the base to the corresponding N-dimethylaminomethylene derivative which is then ammonolyzed. The method was verified by isolation of 9-(2-deoxy-β-D-ribofuranosyl) derivatives of adenine, guanine, 2-chloroadenine, 6-methylpurine, 8-azaadenine, 8-azaguanine, 1-deazaadenine, 3-deazaadenine, 1-(2-deoxy-β-D-ribofuranosyl) derivatives of 5-ethyluracil, 5-fluorouracil, and 9-(2,3-dideoxy-β-D-pentofuranosyl)hypoxanthine, 9-(2,3-dideoxy-β-D-pentofuranosyl)-6-methylpurine, and other nucleosides.

scholarly journals Analysis of rdxA and Involvement of Additional Genes Encoding NAD(P)H Flavin Oxidoreductase (FrxA) and Ferredoxin-Like Protein (FdxB) in Metronidazole Resistance of Helicobacter pylori

2000 ◽  
Vol 44 (8) ◽  
pp. 2133-2142 ◽  
Author(s):  
Dong-Hyeon Kwon ◽  
Fouad A. K. El-Zaatari ◽  
Mototsugu Kato ◽  
Michael S. Osato ◽  
Rita Reddy ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Resistant Strain ◽  
Resistance Mechanisms ◽  
Sensitive Strain ◽  
Metronidazole Resistance ◽  
Genes Encoding ◽  
Resistant Strains ◽  
Flavin Oxidoreductase ◽  
H Pylori

ABSTRACT Metronidazole (Mtz) is a critical ingredient of modern multidrug therapies for Helicobacter pylori infection. Mtz resistance reduces the effectiveness of these combinations. Although null mutations in a rdxA gene that encodes oxygen-insensitive NAD(P)H nitroreductase was reported in Mtz-resistant H. pylori, an intact rdxA gene has also been reported in Mtz-resistant H. pylori, suggesting that additional Mtz resistance mechanisms exist in H. pylori. We explored the nature of Mtz resistance among 544 clinical H. pyloriisolates to clarify the role of rdxA inactivation in Mtz resistance and to identify another gene(s) responsible for Mtz resistance in H. pylori. Mtz resistance was present in 33% (181 of 544) of the clinical isolates. There was marked heterogeneity of resistance, with Mtz MICs ranging from 8 to ≥256 μg/ml.rdxA inactivation resulted in Mtz MICs of up to 32 μg/ml for 6 Mtz-sensitive H. pylori strains and 128 μg/ml for one Mtz-sensitive strain. Single or dual (with rdxA) inactivation of genes that encode ferredoxin-like protein (designatedfdxB) and NAD(P)H flavin oxidoreductase (frxA) also increased the MICs of Mtz for sensitive and resistant strains with low to moderate levels of Mtz resistance. fdxB inactivation resulted in a lower level of resistance than that from rdxAinactivation, whereas frxA inactivation resulted in MICs similar to those seen with rdxA inactivation. Further evidence for involvement of the frxA gene in Mtz resistance included the finding of a naturally inactivated frxA but an intact rdxA in an Mtz-resistant strain, complementation of Mtz sensitivity from an Mtz-sensitive strain to an Mtz-resistant strain or vice versa by use of naturally inactivated or functionalfrxA genes, respectively, and transformation of an Mtz-resistant Escherichia coli strain to an Mtz sensitive strain by a naturally functional frxA gene but not an inactivated frxA gene. These results are consistent with the hypothesis that null mutations in fdxB,frxA, or rdxA may be involved in Mtz resistance.

Synthesis, antitrypanosomal and antimycobacterial activities of coumarinic N-acylhydrazonic derivatives

2020 ◽  
Vol 16 ◽  
Author(s):  
Camila Capelini ◽  
Vitória R. F. Câmara ◽  
José D. Figueroa Villar ◽  
Juliana M. C. Barbosa ◽  
Kelly Salomão ◽  
...  
Keyword(s):  
Resistant Strain ◽  
Sensitive Strain ◽  
Moderate Activity ◽  
Active Compounds ◽  
Meaningful Activity ◽  
The World ◽  
Resistant Strains ◽  
Vitro Effect ◽  
Tuberculosis Activity

Background: Near to 5-7 million people are infected with T. cruzi in the world, and about 10,000 people per year die of problems associated to this disease. Method: We reported herein the synthesis, antitrypanosomal and antimycobacterial activities of seventeen coumarinic N-acylhydrazonic derivatives. Results: These compounds were synthesized using methodology with reactions global yields ranging from 46%-70%. T. cruzi in vitro effect were evaluated against trypomastigote and amastigote forms and M. tuberculosis activity were towards H37Rv sensitive strain and resistant strains. Discussion: Against T. cruzi, the more active compounds revealed only moderate activity IC50/96h~20 µM for both trypomastigotes and amastigotes intracellular forms. (E)-2-oxo-N'-(3,4,5-trimethoxybenzylidene)-2H-chromene-3-carbohydrazide showed meaningful activity in INH resistant/RIP resistant strain. Conclusion: These compound acting as multitarget could be good leads for the development of new trypanocidal and bactericidal agents.

Mechanism of pyridoxine 5'-phosphate accumulation in PLPBP protein-deficiency

2022 ◽  
Author(s):  
Tomokazu Ito ◽  
Honoka Ogawa ◽  
Hisashi Hemmi ◽  
Diana M. Downs ◽  
Tohru Yoshimura
Keyword(s):  
De Novo ◽  
Binding Protein ◽  
Vitamin B ◽  
Wild Type ◽  
Salvage Pathway ◽  
Intracellular Accumulation ◽  
Pyridoxal Kinase ◽  
Genetic Studies ◽  
E Coli ◽  
Metabolic Systems

The pyridoxal 5'-phosphate (PLP)-binding protein (PLPBP) plays an important role in vitamin B 6 homeostasis. Loss of this protein in organisms such as Escherichia coli and humans disrupts the vitamin B 6 pool and induces intracellular accumulation of pyridoxine 5'-phosphate (PNP), which is normally undetectable in wild-type cells. The accumulated PNP could affect diverse metabolic systems through inhibition of some PLP-dependent enzymes. In this study, we investigated the as yet unclear mechanism of intracellular accumulation of PNP by the loss of PLPBP protein encoded by yggS in E. coli . Genetic studies using several PLPBP-deficient strains of E. coli lacking known enzyme(s) in the de novo or salvage pathway of vitamin B 6 , which includes pyridoxine (amine) 5'-phosphate oxidase (PNPO), PNP synthase, pyridoxal kinase, and pyridoxal reductase, demonstrated that neither the flux from the de novo pathway nor the salvage pathway solely contributed to the PNP accumulation caused by the PLPBP mutation. Studies with the strains lacking both PLPBP and PNPO suggested that PNP shares the same pool with PMP, and showed that PNP levels are impacted by PMP levels and vice versa . We show that disruption of PLPBP lead to perturb PMP homeostasis, which may result in PNP accumulation in the PLPBP-deficient strains. Importance A PLP-binding protein PLPBP from the conserved COG0325 family has recently been recognized as a key player in vitamin B 6 homeostasis in various organisms. Loss of PLPBP disrupts vitamin B 6 homeostasis and perturbs diverse metabolisms, including amino acid and α-keto acid metabolism. Accumulation of PNP is a characteristic phenotype of the PLPBP deficiency and is suggested to be a potential cause of the pleiotropic effects, but the mechanism of the PNP accumulation was poorly understood. In this study, we show that fluxes for PNP synthesis/metabolism are not responsible for the accumulation of PNP. Our results indicate that PLPBP is involved in the homeostasis of pyridoxamine 5'-phosphate, and its disruption may lead to the accumulation of PNP in PLPBP-deficiency.

In Vitro Activities of StrychnosAlkaloids and Extracts against Plasmodium falciparum

1999 ◽  
Vol 43 (9) ◽  
pp. 2328-2331 ◽  
Author(s):  
Michel Frederich ◽  
Marie-Pierre Hayette ◽  
Monique Tits ◽  
Patrick De Mol ◽  
Luc Angenot
Keyword(s):  
Plasmodium Falciparum ◽  
Resistant Strain ◽  
Inhibitory Concentration ◽  
Sensitive Strain ◽  
Resistant Strains

ABSTRACT The in vitro antimalarial activities of 46 alkaloids and extracts from Strychnos species were evaluated. Two types of quasidimeric alkaloids exhibit high and selective activities againstPlasmodium. Strychnopentamine and isostrychnopentamine were active against chloroquine-sensitive and -resistant strains (50% inhibitory concentration [IC50] ≈ 0.15 μM), while dihydrousambarensine exhibited a 30-fold higher activity against the chloroquine-resistant strain (IC50 = 0.03 μM) than it did against the chloroquine-sensitive strain.

scholarly journals Why sensitive bacteria are resistant to hospital infection control

2017 ◽  
Vol 2 ◽  
pp. 16 ◽  
Author(s):  
Esther van Kleef ◽  
Nantasit Luangasanatip ◽  
Marc J Bonten ◽  
Ben S. Cooper
Keyword(s):  
Hand Hygiene ◽  
Infection Control ◽  
Resistant Strain ◽  
Mechanistic Model ◽  
Antibiotic Use ◽  
Sensitive Strain ◽  
Control Measures ◽  
Infection Control Measures ◽  
Hospital Infection Control ◽  
Resistant Strains

Background: Large reductions in the incidence of antibiotic-resistant strains of Staphylococcus aureus and Clostridium difficile have been observed in response to multifaceted hospital-based interventions. Reductions in antibiotic-sensitive strains have been smaller or non-existent. It has been argued that since infection control measures, such as hand hygiene, should affect resistant and sensitive strains equally, observed changes must have largely resulted from other factors, including changes in antibiotic use. We used a mathematical model to test the validity of this reasoning. Methods: We developed a mechanistic model of resistant and sensitive strains in a hospital and its catchment area. We assumed the resistant strain had a competitive advantage in the hospital and the sensitive strain an advantage in the community. We simulated a hospital hand hygiene intervention that directly affected resistant and sensitive strains equally. The annual incidence rate ratio (IRR) associated with the intervention was calculated for hospital- and community-acquired infections of both strains. Results: For the resistant strain, there were large reductions in hospital-acquired infections (0.1 ≤ IRR ≤ 0.6) and smaller reductions in community-acquired infections (0.2 ≤ IRR ≤  0.9). These reductions increased in line with increasing importance of nosocomial transmission of the strain. For the sensitive strain, reductions in hospital acquisitions were much smaller (0.6 ≤ IRR ≤ 0.9), while communityacquisitions could increase or decrease (0.9 ≤ IRR ≤ 1.2). The greater the importance of the community environment for the transmission of the sensitive strain, the smaller the reductions. Conclusions: Counter-intuitively, infection control interventions, including hand hygiene, can have strikingly discordant effects on resistant and sensitive strains even though they target them equally, following differences in their adaptation to hospital and community-based transmission. Observed lack of effectiveness of control measures for sensitive strains does not provide evidence that infection control interventions have been ineffective in reducing resistant strains.

scholarly journals The interaction of folic acid derivatives in the methylation of homocysteine

1965 ◽  
Vol 97 (2) ◽  
pp. 500-512 ◽  
Author(s):  
JR Guest ◽  
DD Woods
Keyword(s):  
Folic Acid ◽  
Methylenetetrahydrofolate Reductase ◽  
Competitive Interaction ◽  
E Coli ◽  
Independent Synthesis ◽  
Derivatives Of ◽  
Dependent Mechanism

1. The cobalamin-independent synthesis of methionine from serine and homocysteine by ultrasonic extracts of E. coli with tetrahydropteroyltriglutamate as cofactor was inhibited competitively by tetrahydropteroylmonoglutamate and derivatives which were readily converted into this compound. 2. The potency of these inhibitors was directly related to their ability to function as cofactors or substrates in the alternative, cobalamin- dependent mechanism for homocysteine methylation. 3. The cobalamin-dependent and -independent mechanisms of homocysteine methylation were both inhibited by reduced derivatives of aminopterin in a similar manner. 4. It was tentatively concluded that the inhibition was due to a competitive interaction between the folates for N(5)N(10)-methylenetetrahydrofolate reductase.

scholarly journals Why sensitive bacteria are resistant to hospital infection control

2017 ◽  
Vol 2 ◽  
pp. 16 ◽  
Author(s):  
Esther van Kleef ◽  
Nantasit Luangasanatip ◽  
Marc J Bonten ◽  
Ben S. Cooper
Keyword(s):  
Hand Hygiene ◽  
Infection Control ◽  
Resistant Strain ◽  
Mechanistic Model ◽  
Antibiotic Use ◽  
Sensitive Strain ◽  
Control Measures ◽  
Infection Control Measures ◽  
Hospital Infection Control ◽  
Resistant Strains

Background: Large reductions in the incidence of antibiotic-resistant strains of Staphylococcus aureus and Clostridium difficile have been observed in response to multifaceted hospital-based interventions. Reductions in antibiotic-sensitive strains have been smaller or non-existent. It has been argued that since infection control measures, such as hand hygiene, should affect resistant and sensitive strains equally, observed changes must have largely resulted from other factors, including changes in antibiotic use. We used a mathematical model to test the validity of this reasoning. Methods: We developed a mechanistic model of resistant and sensitive strains in a hospital and its catchment area. We assumed the resistant strain had a competitive advantage in the hospital and the sensitive strain an advantage in the community. We simulated a hospital hand hygiene intervention that directly affected resistant and sensitive strains equally. The annual incidence rate ratio (IRR) associated with the intervention was calculated for hospital- and community-acquired infections of both strains. Results: For the resistant strain, there were large reductions in hospital-acquired infections (0.1 ≤ IRR ≤ 0.6) and smaller reductions in community-acquired infections (0.2 ≤ IRR ≤ 0.9). These reductions increased in line with increasing importance of nosocomial transmission of the strain. For the sensitive strain, reductions in hospital acquisitions were much smaller (0.6 ≤ IRR ≤ 0.9), while community acquisitions could increase or decrease (0.9 ≤ IRR ≤ 1.2). The greater the importance of the community environment for the transmission of the sensitive strain, the smaller the reductions. Conclusions: Counter-intuitively, infection control interventions, including hand hygiene, can have strikingly discordant effects on resistant and sensitive strains even though they target them equally. This follows from differences in their adaptation to hospital- and community-based transmission. Observed lack of effectiveness of control measures for sensitive strains does not provide evidence that infection control interventions have been ineffective in reducing resistant strains.

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