Drugs online research references
Biochemistry. 1990 Jun 19;29(24):5797-806.
The role of lysine-234 in beta-lactamase catalysis probed by site-directed mutagenesis.
Ellerby LM, Escobar WA, Fink AL, Mitchinson C, Wells JA.
Department of Chemistry, University of California, Santa Cruz 95064.
Lys-234 has been postulated to participate in beta-lactamase catalysis by acting as an electrostatic anchor for the C3 carboxylate of penicillins [Herzberg, O., & Moult, J. (1987) Science 236, 694-701]. To test this hypothesis, site-directed mutagenesis was used to convert the Lys-234 in Bacillus licheniformis beta-lactamase into Glu-234 or Ala-234. The wild-type, Glu-234, and Ala-234 beta-lactamases have been expressed in Bacillus subtilis and purified to homogeneity. The wild-type, K234E, and K234A enzymes have virtually identical circular dichroism and fluorescence spectra, similar thermal stabilities at neutral pH, and the same susceptibilities to proteolysis, indicating the lack of significant structural perturbation caused by the mutation. At acidic and basic pH the mutant enzymes have the same native circular dichroism as the wild-type enzyme but the thermal stability is significantly different. The mutations cause perturbations of the pK values of the ionizing groups responsible for the pH dependence of the catalytic reaction in both the free enzyme and the E.S complex. As expected, conversion of Lys-234 to Ala or Glu decreased substrate binding (Km) by 1-2 orders of magnitude for several penicillin and cephalosporin substrates at neutral and higher pH. However, at low pH, Km is essentially the same for the K234E and K234A enzymes as for the wild-type enzyme. Furthermore, decreases of 2-3 orders of magnitude in kcat were also observed, indicating substantial effects on the transition-state binding, as well as on ground-state binding. Surprisingly, changing the C3 carboxylate of phenoxymethylpenicillin to a hydroxymethyl group led to little difference in kinetic properties with the K234E or K234A enzyme. The results of this investigation indicate the Lys-234 is an important active-site residue involved in both ground-state and transition-state binding.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=1974463&dopt=Abstract
Obstet Gynecol. 1990 Jan;75(1):18-21.
Accumulation of penicillin in vaginal fluid.
Sjoberg I, Hakansson S, Holm SE.
Department of Obstetrics and Gynecology, University Hospital, Umea, Sweden.
The excretion of phenoxymethylpenicillin in vaginal fluid was determined in five women after intake of a single dose of 1 g phenoxymethylpenicillin and in five women on a 10-day medication scheme with 1 g twice daily. After the single dose, there was a steady increase of penicillin in vaginal secretion during the following 3 hours. During the same period, the concentrations in serum and saliva peaked and started to decline. Fifteen hours after intake, vaginal fluid contained more than 1 mg/L, whereas no activity was found in serum or saliva. During the 10-day course of treatment, vaginal concentrations ranged between 2-3 mg/L. The drug was not eliminated from the vagina until the second day after ceasing medication. The accumulation and slow pharmacokinetics of phenoxymethylpenicillin in the vagina may be explained by the countercurrent vascular system supplying the internal genitalia and upper vagina. The effect of the high concentrations of penicillin on the vaginal microflora is discussed.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2104967&dopt=Abstract
J Infect Dis. 1990 Feb;161(2):261-5.
Penicillin tolerance in Arcanobacterium haemolyticum.
Nyman M, Banck G, Thore M.
Department of Infectious Diseases, Malmo General Hospital, University of Lund, Sweden.
It was previously found that Arcanobacterium haemolyticum, which can cause tonsillitis with exanthema, is not eradicated from the pharynx by administration of phenoxymethylpenicillin, despite minimum inhibitory concentration values of 0.015-1.0 micrograms/ml. Therefore, recent clinical isolates were studied for penicillin tolerance by using a disk diffusion screening test and a pour plate assay. Macrobroth dilution minimum inhibitory and bactericidal concentrations and antibiotic kill kinetics were determined for 4 isolates. Tolerance was present in 38 of 40 clinical isolates with the disk diffusion assay. With the pour plate assay all 40 isolates were tolerant, 34 of them highly tolerant. The presence of the tolerant phenotype was confirmed by macrobroth dilution assays. It is concluded that A. haemolyticum is often penicillin-tolerant, suggesting that phenoxymethylpenicillin administration would be ineffective in eradicating A. haemolyticum from the pharynx.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2105360&dopt=Abstract
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