David Warhurst - Academia.edu (original) (raw)
Papers by David Warhurst
Transactions of the Royal Society of Tropical Medicine and Hygiene, 2003
Planta Medica, 1995
A new benzoquinone (1-hydroxybenzoisochromanquinone) and benz [g]isoquinoline-5, 10-dione have be... more A new benzoquinone (1-hydroxybenzoisochromanquinone) and benz [g]isoquinoline-5, 10-dione have been isolated from the woody parts of Psychotria camponutans, as a result of bioactivity-guided fractionation. The compounds were characterized by UV, IR, EI-mass, 1H-, and 13C-NMR, and HETCOR NMR spectroscopy. Both compounds, together with acetylbenzoisochromanquinone, showed in vitro strong activity against brine shrimp, KB cells, and chloroquine-resistant P. falciparum.
Molecular and Biochemical Parasitology, 1997
Resistance of Plasmodium falciparum to antifolate chemotherapy is a significant problem where com... more Resistance of Plasmodium falciparum to antifolate chemotherapy is a significant problem where combinations such as Fansidar (pyrimethamine-sulfadoxine; PYR-SDX) are used in the treatment of chloroquine-resistant malaria. Antifolate resistance has been associated with variant sequences of dihydrofolate reductase (DHFR) and dihydropteroate synthetase (DHPS), the targets of PYR and SDX respectively. However, while the nature and distribution of mutations in the dhfr gene are well established, this is not yet the case for dhps. We have thus examined by DNA sequence analysis 141 field samples from several geographical regions with differing Fansidar usage (West and East Africa, the Middle East and Viet Nam) to establish a database of the frequency and repertoire of dhps mutations, which were found in 60% of the samples. We have also simultaneously determined from all samples their dhfr sequences, to better understand the relationship of both types of mutation to Fansidar resistance. Whilst the distribution of mutations was quite different across the regions surveyed, it broadly mirrored our understanding of relative Fansidar usage. In samples taken from individual patients before and after drug treatment, we found an association between the more highly mutated forms of dhps and/or dhfr and parasites that were not cleared by antifolate therapy. We also report a novel mutation in a Pakistani sample at position 16 of DHFR (A16S) that is combined with the familiar C59R mutation, but is wild-type at position 108. This is the first observation in a field sample of a mutant dhfr allele where the 108 codon is unchanged.
Antimicrobial Agents and Chemotherapy, 2011
ABSTRACT Community files, PlasmoDB 25.11.14 Homology Model (WT441S1.pdb) of P. falciparum K13 Kel... more ABSTRACT Community files, PlasmoDB 25.11.14 Homology Model (WT441S1.pdb) of P. falciparum K13 Kelch propeller. Homology protein Model of Plasmodium falciparum K13 Kelch propeller sequence (Coding sequence PF3D7_1343700.) Made in Phyre2. (http:www.sbg.bio.ic.ac.uk/phyre2/PD2/) Kelley and Sternberg 2009. Protein structure prediction on the web: A case study.... Nat Protoc. 2009 4(3): 363-71 After preparation through PHYRE the side-chain rotamers in the final model were optimized using Andante (RE Smith et al. 2007. Andante: reducing side-chain rotamer search space during comparative modeling using environment-specific substitution probabilities. Bioinformatics, 23: (9) 1099-1105) Templates employed: 6 Templates for phyre model 2XN4 human Mayven KLHL2 Canning et al 2013 1X2R human keap1 Padmanabhan2006 2VPJ human KLHL12 Canning 2013 4ASC human kbtbd5 Canning 2013 1ZGK human keap1 Beamer et al 2005 2WOZ KRP1 rat Pseudopodial extension. Gray et al 2009 Total Q-MEAN Score: 0.730 (Z-Score =-0.44) I think this will be of interest to those working on modelling the P. falciparum and related Kelch propellers, as the beta strands of the classical propeller are retained. This work was carried out with the encouragement of Michael Miles and Colin Sutherland at the London School of Hygiene and Tropical Medicine, London WC1E 7HT UK. 2014-11-25 05:17:48 david warhurst london School of hygiene and tropical medicine Uploaded to Community files, PlasmoDB 25.11.14
Trends Pharmacol Sci, 1985
Trends in Pharmacological Sciences, 1985
Transactions of the Royal Society of Tropical Medicine and Hygiene, 1990
Transactions of the Royal Society of Tropical Medicine and Hygiene, 1985
Rabbit antiserum to cultured trophozoites of Giardia intestinalis (G. lamblia) was used to detect... more Rabbit antiserum to cultured trophozoites of Giardia intestinalis (G. lamblia) was used to detect organisms in jejunal biopsies using the PAP immunoperoxidase technique. In 30 sections examined from seven cases of giardiasis associated with histological changes in malabsorption, trophozoites were seen in the lamina propria in one instance, although they were otherwise seen in the intestinal lumen and surface mucus. One anti-Giardia serum reacted with the neutrophil polymorphs in all infected jejunal biopsies, and in jejunal and rectal biopsies from patients not suffering from giardiasis. The reaction with Giardia and with polymorphs could be absorbed out using washed Giardia trophozoites but not with preparations of bacteria.
International Journal for Parasitology, 1994
Antibiotic Resistance from Genes to Global Prevalence, Oct 31, 2010
Antibiotic Resistance from Genes to Global Prevalence, Nov 6, 2013
Eye, 1990
Successful medical therapy of Acanthamoeba keratitis has been reported with combination therapy; ... more Successful medical therapy of Acanthamoeba keratitis has been reported with combination therapy; topical Brolene and neomycin. Resistance has not so far been identified as a problem, but was the basis for recurrent disease observed in a patient with bilateral infection. Eradication of amoebae was finally achieved following prolonged topical therapy and two corneal grafts in each eye. Topical anti-amoebic therapy with paromomycin, benzethonium chloride, clotrimazole and R11/29 (a phenanthridinium compound), was continued for three months post-operatively. No further recurrences occurred during 14 months' follow-up. Drug sensitivities were performed for three isolates of Acanthamoeba sp (group II) which demonstrated the development of resistance to Brolene and arsenic. In addition, the resistant isolates were temperature-sensitive mutants which would not grow at temperatures above 30 degrees C. This could explain 'culture-negative' results in some cases of clinical recurrence when incubation of laboratory samples had only been performed at 37 degrees C.
Transactions of the Royal Society of Tropical Medicine and Hygiene, Jul 1, 2001
Recent studies on resistance to blood schizontocides in Plasmodium falciparum give a rational bas... more Recent studies on resistance to blood schizontocides in Plasmodium falciparum give a rational basis for the use of artemisinins combined with arylaminoalcohols for the treatment of uncomplicated chloroquineresistant malaria in Africa. In areas where such combinations are introduced, there is reason to believe that the continued use of chloroquine in the community will help protect the new drugs from resistance. In view of several laboratory studies, combinations of artemisinins with antifolates or chloroquine pose a risk of antagonistic interaction. This can be avoided by use of the artemisinin and the companion drug sequentially.
Transactions of the Royal Society of Tropical Medicine and Hygiene, 2003
Planta Medica, 1995
A new benzoquinone (1-hydroxybenzoisochromanquinone) and benz [g]isoquinoline-5, 10-dione have be... more A new benzoquinone (1-hydroxybenzoisochromanquinone) and benz [g]isoquinoline-5, 10-dione have been isolated from the woody parts of Psychotria camponutans, as a result of bioactivity-guided fractionation. The compounds were characterized by UV, IR, EI-mass, 1H-, and 13C-NMR, and HETCOR NMR spectroscopy. Both compounds, together with acetylbenzoisochromanquinone, showed in vitro strong activity against brine shrimp, KB cells, and chloroquine-resistant P. falciparum.
Molecular and Biochemical Parasitology, 1997
Resistance of Plasmodium falciparum to antifolate chemotherapy is a significant problem where com... more Resistance of Plasmodium falciparum to antifolate chemotherapy is a significant problem where combinations such as Fansidar (pyrimethamine-sulfadoxine; PYR-SDX) are used in the treatment of chloroquine-resistant malaria. Antifolate resistance has been associated with variant sequences of dihydrofolate reductase (DHFR) and dihydropteroate synthetase (DHPS), the targets of PYR and SDX respectively. However, while the nature and distribution of mutations in the dhfr gene are well established, this is not yet the case for dhps. We have thus examined by DNA sequence analysis 141 field samples from several geographical regions with differing Fansidar usage (West and East Africa, the Middle East and Viet Nam) to establish a database of the frequency and repertoire of dhps mutations, which were found in 60% of the samples. We have also simultaneously determined from all samples their dhfr sequences, to better understand the relationship of both types of mutation to Fansidar resistance. Whilst the distribution of mutations was quite different across the regions surveyed, it broadly mirrored our understanding of relative Fansidar usage. In samples taken from individual patients before and after drug treatment, we found an association between the more highly mutated forms of dhps and/or dhfr and parasites that were not cleared by antifolate therapy. We also report a novel mutation in a Pakistani sample at position 16 of DHFR (A16S) that is combined with the familiar C59R mutation, but is wild-type at position 108. This is the first observation in a field sample of a mutant dhfr allele where the 108 codon is unchanged.
Antimicrobial Agents and Chemotherapy, 2011
ABSTRACT Community files, PlasmoDB 25.11.14 Homology Model (WT441S1.pdb) of P. falciparum K13 Kel... more ABSTRACT Community files, PlasmoDB 25.11.14 Homology Model (WT441S1.pdb) of P. falciparum K13 Kelch propeller. Homology protein Model of Plasmodium falciparum K13 Kelch propeller sequence (Coding sequence PF3D7_1343700.) Made in Phyre2. (http:www.sbg.bio.ic.ac.uk/phyre2/PD2/) Kelley and Sternberg 2009. Protein structure prediction on the web: A case study.... Nat Protoc. 2009 4(3): 363-71 After preparation through PHYRE the side-chain rotamers in the final model were optimized using Andante (RE Smith et al. 2007. Andante: reducing side-chain rotamer search space during comparative modeling using environment-specific substitution probabilities. Bioinformatics, 23: (9) 1099-1105) Templates employed: 6 Templates for phyre model 2XN4 human Mayven KLHL2 Canning et al 2013 1X2R human keap1 Padmanabhan2006 2VPJ human KLHL12 Canning 2013 4ASC human kbtbd5 Canning 2013 1ZGK human keap1 Beamer et al 2005 2WOZ KRP1 rat Pseudopodial extension. Gray et al 2009 Total Q-MEAN Score: 0.730 (Z-Score =-0.44) I think this will be of interest to those working on modelling the P. falciparum and related Kelch propellers, as the beta strands of the classical propeller are retained. This work was carried out with the encouragement of Michael Miles and Colin Sutherland at the London School of Hygiene and Tropical Medicine, London WC1E 7HT UK. 2014-11-25 05:17:48 david warhurst london School of hygiene and tropical medicine Uploaded to Community files, PlasmoDB 25.11.14
Trends Pharmacol Sci, 1985
Trends in Pharmacological Sciences, 1985
Transactions of the Royal Society of Tropical Medicine and Hygiene, 1990
Transactions of the Royal Society of Tropical Medicine and Hygiene, 1985
Rabbit antiserum to cultured trophozoites of Giardia intestinalis (G. lamblia) was used to detect... more Rabbit antiserum to cultured trophozoites of Giardia intestinalis (G. lamblia) was used to detect organisms in jejunal biopsies using the PAP immunoperoxidase technique. In 30 sections examined from seven cases of giardiasis associated with histological changes in malabsorption, trophozoites were seen in the lamina propria in one instance, although they were otherwise seen in the intestinal lumen and surface mucus. One anti-Giardia serum reacted with the neutrophil polymorphs in all infected jejunal biopsies, and in jejunal and rectal biopsies from patients not suffering from giardiasis. The reaction with Giardia and with polymorphs could be absorbed out using washed Giardia trophozoites but not with preparations of bacteria.
International Journal for Parasitology, 1994
Antibiotic Resistance from Genes to Global Prevalence, Oct 31, 2010
Antibiotic Resistance from Genes to Global Prevalence, Nov 6, 2013
Eye, 1990
Successful medical therapy of Acanthamoeba keratitis has been reported with combination therapy; ... more Successful medical therapy of Acanthamoeba keratitis has been reported with combination therapy; topical Brolene and neomycin. Resistance has not so far been identified as a problem, but was the basis for recurrent disease observed in a patient with bilateral infection. Eradication of amoebae was finally achieved following prolonged topical therapy and two corneal grafts in each eye. Topical anti-amoebic therapy with paromomycin, benzethonium chloride, clotrimazole and R11/29 (a phenanthridinium compound), was continued for three months post-operatively. No further recurrences occurred during 14 months' follow-up. Drug sensitivities were performed for three isolates of Acanthamoeba sp (group II) which demonstrated the development of resistance to Brolene and arsenic. In addition, the resistant isolates were temperature-sensitive mutants which would not grow at temperatures above 30 degrees C. This could explain 'culture-negative' results in some cases of clinical recurrence when incubation of laboratory samples had only been performed at 37 degrees C.
Transactions of the Royal Society of Tropical Medicine and Hygiene, Jul 1, 2001
Recent studies on resistance to blood schizontocides in Plasmodium falciparum give a rational bas... more Recent studies on resistance to blood schizontocides in Plasmodium falciparum give a rational basis for the use of artemisinins combined with arylaminoalcohols for the treatment of uncomplicated chloroquineresistant malaria in Africa. In areas where such combinations are introduced, there is reason to believe that the continued use of chloroquine in the community will help protect the new drugs from resistance. In view of several laboratory studies, combinations of artemisinins with antifolates or chloroquine pose a risk of antagonistic interaction. This can be avoided by use of the artemisinin and the companion drug sequentially.