The inhibition in vitro of bacterial DNA polymerases and RNA polymerase by antimalarial 8-aminoquinolines and by chloroquine

Whichard, Leona P.; Washington, Mildred E.; Holbrook, David

doi:10.1016/0005-2787(72)90329-2

Cited by 33 publications

(12 citation statements)

References 13 publications

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“…Moreover, in vitro data have suggested that the effects of hydroxychloroquine might be generalized for Borrelia burgdorferi (31) and all intracellular organisms that multiply in acidic environments (32). Although antimalarials are generally inactive against most extracellular bacterial species (33), a direct antibacterial effect has been demonstrated, with an in vitro inhibitory effect on the bacterial DNA polymerase of E. coli and Micrococcus luteus (34,35). However, the results of a recent study indicated that quinine did not show any antibacterial activity against E. coli (33).…”

Section: Discussionmentioning

confidence: 99%

Abnormal Weight Gain and Gut Microbiota Modifications Are Side Effects of Long-Term Doxycycline and Hydroxychloroquine Treatment

Angelakis

Million

Kankoe

et al. 2014

Antimicrob Agents Chemother

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b Doxycycline has been proposed for the treatment of malnourished children in developing countries, and its use has been associated with weight gain in healthy volunteers. No previous studies have assessed abnormal weight gain as a putative side effect of long-term doxycycline treatment; thus, the objective of the present study was to characterize this phenomenon. We also analyzed the role of the gut microbiota in this effect. We assessed changes in the body mass index in Q fever endocarditis patients treated with doxycycline and hydroxychloroquine and healthy individuals with no antibiotic treatment. Abnormal weight gain was defined as a gain in weight above that of the controls. The fecal samples were examined using molecular assays for Methanobrevibacter smithii, Bacteroidetes, Firmicutes, Escherichia coli, Lactobacillus, Lactobacillus reuteri, and total bacterial concentrations. We examined 82 patients, including 48 patients with Q fever endocarditis and 34 controls. Approximately 23% of the treated patients showed abnormal weight gain (P ‫؍‬ 0.001). Patients treated with doxycycline and hydroxychloroquine presented significantly lower concentrations of Bacteroidetes (P ‫؍‬ 0.002), Firmicutes (P ‫؍‬ 0.01), and Lactobacillus (P ‫؍‬ 0.02). The linear regression analysis revealed that the duration of treatment was significantly associated with a decrease in Bacteroidetes (P ‫؍‬ 0.0001), Firmicutes (P ‫؍‬ 0.002), and total bacteria (P < 0.00001). Abnormal weight gain is a side effect of long-term doxycycline and hydroxychloroquine treatment. Gut microbiota modifications at the phylum level could play an instrumental role in this effect. We highlight the need for specific nutritional care in patients undergoing long-term antibiotic treatment, particularly treatment involving the use of doxycycline.

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Section: Discussionmentioning

confidence: 99%

Abnormal Weight Gain and Gut Microbiota Modifications Are Side Effects of Long-Term Doxycycline and Hydroxychloroquine Treatment

Angelakis

Million

Kankoe

et al. 2014

Antimicrob Agents Chemother

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“…Chloroquine, quinine, and related 4-aminoquinolines are effective drugs against malarial infection, and the ability of chloroquine to form complexes with DNA is well documented (Blodgett and Yielding, 1968;Yielding et al, 1971). Chloroquine, mepacrine, and other quinoline derivatives are potent inhibitors of DNA and RNA polymerase (O'Brien et al, 1966;Whichard et al, 1972), as well as DNA and RNA synthesis in P. knowlesi (Gutteridge et al, 1972). Chloroquine and quinine inhibited 50% of DNA topoisomerase II activity of drugsensitive and drug-resistant P. berghei at a 40 lg/reaction mixture concentration.…”

Section: Resultsmentioning

confidence: 99%

Oxygenated chalcones and bischalcones as a new class of inhibitors of DNA topoisomerase II of malarial parasites

et al. 2007

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The DNA topoisomerase (topo) II of chloroquine-sensitive and chloroquine-resistant strains of the rodent malaria parasite P. berghei were utilized as a target for testing of antimalarial compounds. Compounds belonging to the bischalcone and chalcone series significantly inhibited enzyme activity and percentage parasitaemia of chloroquine-sensitive and chloroquine-resistant strains of P. berghei. Compounds 1a, 1b, 2a, 2b, and 2c showed 100% inhibition while compounds 2h and 2i showed 60% and 63% inhibition of topoisomerase II activity of the chloroquinesensitive strain, respectively. Compounds 2a, 2b, and 2d significantly inhibited the topo II activity of chloroquine-resistant strain. Compounds 2g and 2e specifically inhibited the topo II activity of the chloroquine-resistant strain of P. berghei with no effect on the chloroquine-sensitive strain. The in vitro topo II inhibition by chalcone and bischalcone analogs can be correlated with their in vivo antimalarial activity, as compounds 2c and 2h inhibited both in vitro activity of topo II and in vivo parasitaemia of the chloroquine-sensitive strain of P. berghei. In the chloroquine-resistant strain, compounds 2c, 2e, 2g, and 2i inhibited activity against both in vitro topo II and parasitaemia in vivo. The significant inhibition of topo II in the chloroquine-resistant strain by some of the analogs suggests the utilization of these structures for the synthesis of compounds active against chloroquine-resistant malarial parasites.

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“…bAdx: adrenalectomized rat. (Whichard et al, 1972). The lack of effect of chloroquine or primaquine on protein synthesis under the conditions in these studies eliminates inhibition of energy production as a possible cause of this inhibition of precursor incorporation into nucleic acids.…”

Section: Incorporation Of Uridine Orotate and Adeninementioning

confidence: 87%

“…Chloroquine and primaquine inhibit the incorporation of radioactive precursors into DNA and/or RNA in non-mammalian eukaryotic cells (Schellenberg & Coatney, 1961;Polet & Barr, 1968; Dyke, Szustkiewicz, Lantz & Saxe, 1969;Conklin & Chou, 1972a) and in cultured mammalian cells (Gabourel, 1963;Epstein, Fukuyama & Epstein, 1971). In vitro, chloroquine and primaquine inhibit DNA and RNA polymerases from bacterial sources (Cohen & Yielding, 1965;O'Brien, Olenick & Hahn, 1966;Whichard, Washington & Holbrook, 1972;Marquez, Cranston, Ruddon & Burckhalter, 1974) and from Tetrahymena pyriformis (Conklin, Heu and Chou, 1973). Moreover, various steps in polypeptide synthesis in eukaryotic cells are inhibited by chloroquine or primaquine (Ilan & Ilan, 1969;Landez, Roskoski & Coppoc, 1969;Roskoski & Jaskunas, 1972;Lefler, Lilja & Holbrook, 1973).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Precursor Incorporation Into Nucleic Acids of Mammalian Tissues by Antimalarial Aminoquinolines

Field

Gibson

Holbrook

et al. 1978

British J Pharmacology

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1 Chloroquine, primaquine and ethidium inhibited thymidine incorporation into deoxyribonucleic acid of rat tissues when administered concurrently with the labelled precursor. 2 Chloroquine and primaquine inhibited the incorporation of uridine and adenine, but not orotate, into various ribonucleic acid fractions of liver of rats and mice. These drugs had no effect on leucine incorporation into hepatic protein in rats or mice. 3 Although chloroquine and primaquine are active against different stages in the life cycle of the malarial parasites, the two aminoquinolines exert similar effects in rodent tissues.

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The inhibition in vitro of bacterial DNA polymerases and RNA polymerase by antimalarial 8-aminoquinolines and by chloroquine

Cited by 33 publications

References 13 publications

Abnormal Weight Gain and Gut Microbiota Modifications Are Side Effects of Long-Term Doxycycline and Hydroxychloroquine Treatment

Abnormal Weight Gain and Gut Microbiota Modifications Are Side Effects of Long-Term Doxycycline and Hydroxychloroquine Treatment

Oxygenated chalcones and bischalcones as a new class of inhibitors of DNA topoisomerase II of malarial parasites

Inhibition of Precursor Incorporation Into Nucleic Acids of Mammalian Tissues by Antimalarial Aminoquinolines

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