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Marcou,M; Holton,J;Roitt,I; Rademacher,T
Efficacy of Amoxycillin linked to gold nanoparticles compared to free amoxycillin against H. pylori Marcou,M; Holton,J;Roitt,I; Rademacher,T Windeyer Institute of Medical Science, University College London, London, UK
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AIMS The aim was to assess the efficacy of amoxycillin when linked to gold nanoparticle (gnp) against Helicobacter pylori
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BACKGROUND 1 Helicobacter pylori is one of the commonest infections in the world. About 20% of infected persons may develop serious gastroduodenal disease including peptic ulcers and about 1% may develop gastric cancer. Although the incidence of Helicobacter pylori infection is falling in industrialized countries it remains an important pathogen globally and even in industrialized countries, as the prevalence of antibiotic resistance increases, the eradication rate of the organism is falling with consequent failure to cure the ulcer disease.
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BACKGROUND 2 Helicobacter pylori is currently treated with a PPI and a combination of 2 antibiotics: Amoxycillin plus either metronidazole or clarithromycin. The eradication rate is in the region of 90-95%. However, owing to antibiotic resistance, particularly metronidazole and clarithromycin the eradication rate may be as low as 75%. Metronidazole resistance is high in some countries showing 50% resistant strains whilst clarithromycin resistant rate varies from 12-25%. Amoxycillin resistance is rare. For this reason we have tested amoxycillin linked to gold nanoparticles to assess the activity of the antibiotic
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RATIONALE As a proof of principle our goal is to attach ligands that specifically binds to H. pylori to gnp’s along with appropriate antibiotics. We anticipate this approach to increase the concentration of antibiotic at the micro-organism without causing damage to the host, disturbing the hosts' normal protective flora nor putting a selective antimicrobial pressure on the local or global ecosystem leading to the development of further drug resistance. As a first step we have tested the efficacy of amoxycillin linked to gnp’s.
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METHOD 1 Molecules in the form of an S-S-linked dimer can be reacted with a gold salt to produce the nanoparticle with a gold atom core having the selected molecule linked to its surface by an S-bond. The gnp is coated with glucose and has aliphatic S-H linker molecules attached to which the amoxycillin has been linked Gold nanoparticle-amoxycillin having different loadings of amoxycillin : glucose 21(2:1) 18-20( 3:1) 22 (4:1) and 23 (9:1) were tested against soluble amoxycillin at equivalent amoxycillin concentrations ranging from mg/L.
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TEM of GNP’s
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Amoxycillin-GNP Linkage
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GNP with Amox at various ratios
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METHOD 2 A suspension of H. pylori J99 (MIC 0.6 mg/L) was made in sterile water to approx 108 (final conc 107) Serial dilutions of amoxycillin at 0.26, 0.20,0.1 and 0.08 were prepared GNP’s 21,22,23,18,19,20 were used 200 microL of sterile water as control 20 microL microL of H. pylori suspension was added to 180 microL of amoxycillin, gnp-amoxycillin and gnp without amoxycillin 50 microL were plated at T0, T60, T120 onto Columbia blood agar The plates were incubated in gas jar with campyPak for 5 days
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RESULTS C1 C2 0.26 0.2 0.1 0.08 T0 1.9 x 106 T60 8.6 x 105 1.9 x 105 8.5 x 105 3.7 x 106 1.0 x 105 1.2 x 106 T120 5.2 x 105 1.2 x 105 4.8 x 105 2.3 x 106 7.1 x 105 2.0 x 106 21 22 23 18 19 20 1.3 x 104 2.0x 105 6.6 x 105 4.4 x 105 NG 3.2 x 105 3.1 x 105 2.6 x 105 4.1 x 105 3.5 x 105
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RESULTS 2
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CONCLUSIONS Amoxycillin linked to gold nanoparticles has equivalent activity to free amoxycillin against Helicobacter pylori. There is some suggestion that gnp21 may have greater activity compared to free amoxycillin
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Future Prospects Future studies will investigate:-
the bactericidal efficacy of amoxycillin + domain antibodies against BabA (or Leb hexasaccharide) linked to gnp against Helicobacter pylori the efficacy of domain antibodies against BabA (or Leb hexasaccharide) linked to gnp the use of gnp-linked ligands +/- antibiotics against other micro-organisms eg Candida
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REFERENCES De Bernadis,F; Liu,H; O'Mahony,R; La Valle,R; Bartollino,S; Sandini,S; Grant,S; Brewis,N; Tomlinson,I; Basset,C; Holton,J; Roitt,I; Cassone,A. Human domain antibodies against virulence traits of Candida albicans inhibit fungal adherence to vaginal epithelium and protects against experimental vaginal candidiasis. J. Infect. Dis : Justine Younson, Rachel O’Mahony, Haiqun Liu, Steven Grant, Colin Campion, Jeanna Bugaystova, Susanne Vikström, Rolf Sjöstrom, Dino Vaira, Lisa Jennings, Thomas Borèn, Charles G. Kelly, Ivan M. Roitt, John Holton. A human domain antibody and Lewisb–glycoconjugate that inhibit binding of Helicobacter pylori to Lewisb receptor and inhibit bacterial adhesion to human gastric epithelium. IN PREP
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