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ABSTRACT: 6,9-Disubstituted purines and 7-deazapurines are known to be powerful inhibitors of Mycobacterium tuberculosis (Mtb) in vitro. Analogs modified in the six-membered ring (imidazopyridines, pyrrolopyridines, benzimidazoles, and indoles) were synthesized and evaluated as Mtb inhibitors. The targets were prepared by functionalization on the bicyclic heterocycle or from simple pyridines. The results reported herein, indicate that the purine N-1, but not N-3, is important for binding to the unknown target. The 3-deazapurines appears to be slightly more active compared to the parent purines and slightly less active than their 7-deazapurine isomers. Removal of both the purine N-3 and N-7 did not result in further enhanced antimycobacterial activity but the toxicity towards mammalian cells was increased. Both 3-deaza and 3,7-dideazapurines exhibited a modest activity against of the Mtb isolate in the state of non-replicating persistence.
Bioorganic & medicinal chemistry 06/2011; 19(11):3483-91. · 2.82 Impact Factor
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ABSTRACT: Culture-dependent and -independent methods were used to investigate the small eukaryote composition of raw and finished waters in the Norwegian cities of Oslo, Tromsø, Fredrikstad and Oppegård. Probes with general applicability to the 18S rRNA genes of the small eukaryote consortium were used for PCR-denaturing gradient gel electrophoresis (DGGE), and in the generation of clone libraries using the TOPO™ cloning and sequencing system. The chosen probes invariably gave a single band in agarose gel electrophoresis, indicating amplification of an area of similar size. DGGE and cloning analyses resolved the bands into components representing many unique amplicons. Diversity and composition in the collection were studied by DNA-sequencing, and visual examination of DGGE patterns. The cloning approach enabled the putative identification of a total of approximately 100 unique small eukaryotes. The major fraction of these represented ciliated and flagellated protozoal species. This was in keeping with the findings from protozoal cultivation. DNA from a number of multicellular eukaryotes was also detected. Amoebal and fungal DNA was rarely found. The latter may indicate a low incidence or a bias in the analysis technique. The population of small eukaryotes appears typical for pristine waters and no primary pathogens were detected by culture-independent techniques. However, the potentially pathogenic protozoa Acanthamoeba castellanii was grown on one occasion from Oslo's drinking water. DGGE allowed the identification of fewer amplicons (by excision and sequencing of bands) than by the cloning-transformation approach. The DGGE analysis revealed clear similarities between the compositions of the raw and treated waters, indicating that cells or DNA in the raw water pass through the treatment trains. Protozoal culture and heterotrophic plate count analysis consistently revealed viable cells in both raw and treated waters in Oslo. This indicates that a fraction of the clone library represents eukaryotic species surviving the treatment trains. The analyses here presented represent the first published study of the general small eukaryotic fraction of the Capital's drinking water, and those of three other Norwegian cities. We suggest that DGGE profiles may have a value in judging physical treatment efficacy (removal of cells), but that direct cloning and sequencing studies is more amenable for characterization of uncultured microbes.
Water Research 02/2011; 45(8):2527-38. · 4.86 Impact Factor
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ABSTRACT: The microbiological quality of the five leading brands of Norwegian bottled still waters was investigated. All brands were free for the enteric indicator organisms and named pathogens whose absence is demanded in current quality directives. The relatively nutrient-poor agar R₂A revealed large heterogeneous bacterial populations which grew slowly, or not at all, on clinical media specified for use in substrate-utilization approaches to identification. The main approach used for identification was cultivation of microbes on R₂A, followed by amplification and partial sequencing of 16S rDNA genes. The identity of the heterotrophic plate count of the brands differed significantly to that found in many other similar studies with respect to the dominating species. The bacterial flora was dominated by beta- and alphaproteobacteria most of which were psychrotolerant. Several brands contained Sphingomonas and large populations of Methylobacterium species which have been associated with a variety of opportunistic infections of immunocompromised hosts. Analysis of the isolated strains' nutritional capabilities using the Biolog GN2® system, gave in most instances low positive scores, and strain identifications using the system were generally inconclusive. Measures of assimilable organic carbon in the water revealed that some brands contained levels higher than those which have been associated with biological stability and restricted or no growth of heterotrophs in distribution systems. The relationship between assimilable organic carbon and R₂A plate counts was significant and moderately positive for bottled waters. Assimilable organic carbon correlated strongly with the survival time of Escherichia coli when introduced into bottles as a contaminant. Those brands having high values (~100 μg/L) supported protracted survival, but not growth of E. coli, whereas E. coli quickly became nonculturable in brands with low values. Thus measures of assimilable organic carbon may have a particular value in predicting the survival of this and nutritionally similar species of hygienic relevance. Only small numbers of fungi were found. However, one isolate (Aureobasidium pullulans) has been associated with infections of humans.
International journal of food microbiology 01/2011; 144(3):455-63. · 3.01 Impact Factor
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ABSTRACT: Agelasines are 7,9-dialkylpurinium salts found in marine sponges (Agelas sp.), which display a variety of antimicrobial and cytotoxic effects. We have synthesized simplified agelasine analogs modified in the purine 2-position and examined their antimicrobial and anticancer activities. The compounds were screened against Staphylococcus aureus, Escherichia coli, Mycobacterium tuberculosis, Candida krusei, and Candida albicans, protozoa causing tropical diseases (Plasmodium falciparum, Leishmania infantum, Trypanosoma cruzi, and Trypanosoma brucei), a panel of human cancer cell lines (U-937 GTB, RPMI 8226/s, CEM/s, and ACHN) as well as VERO and/or MRC-5 cells. The results indicate that the introduction of a methyl group in the purine 2-position is beneficial for antimycobacterial and antiprotozoal activity, and that amino groups may enhance activity against several cancer cell lines.
Archiv der Pharmazie 01/2011; 344(1):50-5. · 1.71 Impact Factor
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Archiv der Pharmazie 11/2010; 344(1):50 - 55. · 1.71 Impact Factor
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ABSTRACT: Purine analogs modified in the five-membered ring have been synthesized and examined for antibacterial activity against Mycobacterium tuberculosis H(37)Rv in vitro employing the microplate alamar blue assay (MABA). The 9-deaza analogs were only found to be weak inhibitors, but the 8-aza-, 7-deaza- and 8-aza-7-deazapurine analogs studied displayed excellent antimycobacterial activities, some even substantially better than the parent purine. In the 7-deazapurine series, MIC values between 0.08 and 0.35 μM, values comparable or better than the reference drugs used in the study (MIC rifampicin 0.09 μM, MIC isoniazid 0.28 μM and MIC PA-824 0.44 μM). The five most active compounds were also examined against a panel of drug-resistant Mtb strain, and they all retained their activity. The compounds examined were significantly less active against M. tuberculosis in a state of non-replicating persistence (NRP). MIC in the low-oxygen-recovery assay (LORA) ≥ 60 μM. The 7-deazapurines were somewhat more toxic towards mammalian cells, but still the selectivity indexes were excellent. The non-purine analogs exhibit a selective antimycobacterial activity. They were essentially inactive against Staphylococcus aureus and Escherichia coli.
Bioorganic & medicinal chemistry 10/2010; 18(20):7274-82. · 2.82 Impact Factor
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ABSTRACT: Pyrimidine analogs of antimycobacterial purines have been synthesized and their biological activities evaluated. Several 5-formamidopyrimidines exhibited profound activity against Mycobacterium tuberculosis in vitro (IC(90)< or =1.5 microg/mL), and they were essentially inactive against other bacteria.
Bioorganic & medicinal chemistry letters 05/2009; 19(12):3297-9. · 2.65 Impact Factor
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ABSTRACT: Agelasines and agelasimines are antimicrobial and cytotoxic purine derivatives isolated from marine sponges (Agelas sp.). We have synthesized structurally simplified analogs of these natural products starting from beta-cyclocitral. The novel compounds were found to be strong inhibitors of a wide variety of pathogenic microorganisms (incl. Mycobacterium tuberculosis) as well as cancer cell lines. The biological activities were generally in the same range as those previously found for the structurally more complex agelasines and agelasimines isolated in small amounts from natural sources. We also report for the first time that agelasine and agelasimine analogs inhibit growth of protozoa (Acanthamoeba castellanii and Acanthamoeba polyphaga). Acanthamoeba keratitis is an increasingly common and severe corneal infection, closely associated with contact lens wear.
Archiv der Pharmazie 01/2008; 340(12):625-34. · 1.71 Impact Factor
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ABSTRACT: Agelasine and agelasimine derivatives with substantially less complicated terpenoid side chains compared to the naturally occurring compounds have been synthesized and their ability to inhibit growth of microorganisms and cancer cells has been studied. Compounds with excellent activity against cancer cell lines (MIC ca. 1 microM for the most potent compounds), including a drug resistant renal cell line, have been identified. Most compounds studied also exhibited broad spectrum antimicrobial activity including activity against Mycobacterium tuberculosis.
Bioorganic & Medicinal Chemistry 07/2007; 15(12):4016-37. · 2.92 Impact Factor
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ABSTRACT: 1-substituted indolizines with activity against Mycobacterium tuberculosis have been synthesized. The most active compounds carry an hydroxyphenylmethyl- or hydroxyalkyl substituent in the indolizine 1-position. The alkyl chain should be moderately long (C-5 or C-6). Aryl groups in the 2- and 3-position of the indolizine are also required. Removal of the 3-substituent resulted in significant loss of activity. A nitrile substituent in the 7-position is beneficial for both chemical stability and bioactivity. The compounds studied display a narrow antibacterial spectrum and appear to be quite selective antimycobacterial compounds. Moderate activity against certain pathogenic protozoa was also observed.
European Journal of Pharmaceutical Sciences 02/2007; 30(1):26-35. · 3.21 Impact Factor
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Colin Charnock
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ABSTRACT: The number of people obtaining a tattoo has increased markedly in recent years Tattooing is known to present a risk of transfer of bacterial/fungal pathogens and possibly also viral pathogens. Colorants used for tattooing purposes can be heavily contaminated with bacteria, thus presenting a risk for infections. Concerted efforts are being made to remove this threat, including the production and use of cleaner dyes and pigments with enhanced antimicrobial properties.
Challenge tests were used to assess the survival characteristics of bacteria, bacterial endospores, fungal hyphae/spores, and bacteriophage in tattooing colorants.
Bacteria were able to grow to high numbers in some colorants. A recently marketed, preservative-free colorant was shown to have a good hygienic quality and rapidly inactivated added bacteria and fungal spores. Activity against bacterial endospores was also demonstrated. Bacteriophage survived in the product during the 28-day test period.
The present study is the first to document the survival characteristics of vegetative bacteria and endospores, fungi, and bacteriophage (as virus surrogate) in tattooing solutions. The results of the present study readily explain the previously reported high numbers of bacteria in some tattooing colorants. A preservative-free colorant, which was designed in response to recent recommendations of the European Council with respect to chemical content, was also adequately self-preserving with respect to bacterial and fungal growth.
American Journal of Infection Control 07/2006; 34(5):290-5. · 2.40 Impact Factor
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Colin Charnock
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ABSTRACT: To investigate artificial tears containing different preservatives for antimicrobial efficacy. Based on the challenge test outlined in the European Pharmacopoeia, products were tested in their original containers to see whether their component preservative had sufficient activity.
Five brands of over-the-counter artificial tears each containing different preservatives (benzalkonium chloride/EDTA, parabens, chlorobutanol, silver chloride complex, and Purite-stabilized oxychloro complex) were inoculated with test microorganisms (Pseudomonas aeruginosa, Staphylococcus aureus, and Candida albicans). Changes in the microbial start concentration with time were followed by plating onto growth media to provide a measure of the preservative efficacy. In another test, artificial tears were applied to paper disks that were then placed onto agar growth media seeded with microorganisms. Zones of inhibition were measured after incubation.
Only the brand of artificial tears containing benzalkonium chloride/EDTA satisfied the major criteria for antimicrobial preservation for all the test microorganisms. Only a benzalkonium chloride/EDTA-containing disk placed on agar seeded with S. aureus produced a zone of inhibition in the agar diffusion test.
The brand of artificial tears containing benzalkonium chloride/EDTA is suitable for sale in countries adopting the monographs of the European Pharmacopoeia. Other brands would only be suitable for sale if justified reasons for not meeting the major criteria for preservative efficacy can be provided.
Cornea 06/2006; 25(4):432-7. · 1.73 Impact Factor
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ABSTRACT: An improved synthesis of (+)-agelasine D (10) from (+)-manool is reported together with cytotoxic and antibacterial data for agelasine D and structurally close synthetic analogues. These compounds display a broad spectrum of antibacterial activities including effects on M. tuberculosis and Gram-positive and Gram-negative bacteria (both aerobes and anaerobes). They exhibit profound cytotoxic activity against several cancer cells, including a multidrug-resistant cell line. (+)-Agelasine D (10) has been isolated earlier from a marine sponge (Agelas sp.).
Journal of Natural Products 04/2006; 69(3):381-6. · 3.13 Impact Factor
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Colin Charnock
British Journal of General Practice 08/2005; 55(516):560. · 1.83 Impact Factor
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Colin Charnock
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ABSTRACT: Previous studies have shown that toys in waiting rooms of general practice surgeries can be contaminated with potentially pathogenic bacteria. The question was raised as to whether magazines might also be sources of contamination. Swabbing of the front page of 15 magazines from 11 general practice surgeries, followed by analysis for total and specific bacteria, revealed low levels of contamination. Among targeted groups of pathogens only two colonies of Staphylococcus aureus were detected. Magazines do not seem to be potentially important vectors of bacterial transfer in the setting examined.
British Journal of General Practice 02/2005; 55(510):37-9. · 1.83 Impact Factor
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ABSTRACT: A number of diesters of the topical dermatosis treatment azelaic (nonanedioic) acid were prepared and tested for antibacterial effect. Two esters, bis-[(hexanoyloxy)methyl] nonanedioate and especially bis-[(butanoyloxy)methyl] nonanedioate showed promising activity against acne related bacteria in vitro. No activity of azelaic acid was detected in Mueller Hinton II agar at pH 7.3 when using the agar diffusion method, whereas both esters gave zones of growth inhibition. At pH 5.6, activity of azelaic acid was detected. At this pH, the zones of inhibition and MIC values obtained with azelaic acid were smaller than those of bis-[(butanoyloxy)methyl] nonanedioate for all test organisms. A preparation for topical use containing 20% (w/w) bis-[(butanoyloxy)methyl] nonanedioate, and the commercially available Skinoren (20% (w/w) azelaic acid), were compared for antibacterial effect against cutaneous bacteria using contact plate analyses of the skin. Though Skinoren was usually most effective, the differences were not statistically significant. Furthermore, bacteria surviving contact with the topical preparations were invariably more sensitive to the ester than to azelaic acid upon subculturing onto agar (pH 5.6) containing either preparation at 0.2-0.7 mg/ml. This might indicate that other factors, such as the composition of the cream base, mitigate the antibacterial activity of the ester. It is proposed that the pharmacological and microbiological properties of bis-[(butanoyloxy)methyl] nonanedioate are worthy of further study based on an extended screening of acne sufferers.
European Journal of Pharmaceutical Sciences 05/2004; 21(5):589-96. · 3.21 Impact Factor
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Colin Charnock
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ABSTRACT: Obtaining a tattoo has become increasingly popular in recent years. However, the degree to which tattooing represents a health risk in the form of infections is still a matter of debate. The aim of the present study was to investigate the microbial content of tattooing dyes and pigments (colourants).
Microbes present in colourants used for tattooing were counted and identified using standard techniques and rapid identification systems.
Seven of in total twelve colourants contributed by five studios contained bacteria. No fungi were found. Three solutions contained more than 10 8 bacteria/ml, chiefly aerobic, Gram-negative rods including Pseudomonas aeruginosa. No primary pathogens were found, however, the high colony counts found for some samples may represent infectious doses of a wide range of bacteria.
Although required by current regulations to be sterile, a number of colourants were highly contaminated with bacteria. The detection of bacteria in colourants necessitates a review of the studios' internal control procedures. In addition, the appropriate monitoring body should initiate testing of colourants in order to ascertain if these are contaminated at the time of purchase, or become so during use.
Tidsskrift for den Norske laegeforening 05/2004; 124(7):933-5.
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ABSTRACT: Efficient total syntheses of heteromines A and B (antitumor compounds previously isolated from the plant Heterostemma brownii Hayata) from commercially available 2-amino-6-chloropurine have been developed. The synthesis of heteromine A is considerably shorter than the previously reported synthesis, only requiring four steps, whereas the iodide salt of heteromine B was prepared in five steps. Heteromines A and B showed no significant antibacterial activity and therefore appear to be selective toward cancer cell lines.Graphical abstract
Tetrahedron. 65(27):5199-5203.
