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- Borsa, Baris Ata, First Research Engineer, et al.
(författare)
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Therapeutic-oligonucleotides activated by nucleases (TOUCAN) : A nanocarrier system for the specific delivery of clinical nucleoside analogues.
- 2023
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Ingår i: Journal of Controlled Release. - : ELSEVIER. - 0168-3659 .- 1873-4995. ; 361, s. 260-269
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Tidskriftsartikel (refereegranskat)abstract
- Nucleoside analogues have been in clinical use since 1960s and they are still used as the first therapeutic option for several cancers and viral infections, due to their high therapeutic efficacy. However, their wide clinical acceptance has been limited due to their high toxicity and severe side effects to patients. Herein, we report on a nanocarrier system that delivers nucleosides analogues in a target-specific manner, making nucleoside-based therapeutics safer and with the possibility to be used in other human conditions. This system, named, Therapeutic OligonUCleotides Activated by Nucleases" (TOUCAN) combines: i) the recognition power of oligonucleotides as substrates, ii) the use of nucleases as enzymatic biomarkers and iii) the clinical efficacy of nucleoside analogues, in a single approach. As a proof-of-concept, we report on a TOUCAN that is activated by a specific nuclease produced by bacteria and releases a therapeutic nucleoside, floxuridine. We demonstrate, for the first time, that, by incorporating a therapeutic nucleoside analogue into oligonucleotide probes, we can specifically inhibit bacterial growth in cultures. In this study, Staphylococcus aureus was selected as the targeted bacteria and the TOUCAN strategy successfully inhibited its growth with minimal inhibitory concentration (MIC) values ranging from 0.62 to 40 mg/L across all tested strains. Moreover, our results indicate that the intravenous administration of TOUCANs at a dose of 20 mg/kg over a 24-h period is a highly effective method for treating bacterial infections in a mouse model of pyomyositis. Importantly, no signs of toxicity were observed in our in vitro and in vivo studies. This work can significantly impact the current management of bacterial infections, laying the grounds for the development of a different class of antibiotics. Furthermore, it can provide a safer delivery platform for clinical nucleoside therapeutics in any human conditions, such as cancer and viral infection, where specific nuclease activity has been reported.
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| 2. |
- Tellapragada, Chaitanya, et al.
(författare)
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Recurrent bacteremia with Enterococcus faecalis, the clinical findings predicting endocarditis, and genomic characterization of the isolates : a retrospective cohort study
- 2023
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Ingår i: European Journal of Clinical Microbiology and Infectious Diseases. - 0934-9723. ; 42:8, s. 1001-1009
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Tidskriftsartikel (refereegranskat)abstract
- Multiple episodes of Enterococcus faecalis bacteremia (EfsB) may indicate a relapse and be due to an undiagnosed infective endocarditis (IE). The aims were to study the clinical presentation of patients with EfsB with focus on the risk of recurrent infection and IE, identify potential improvements of the management, and to investigate whether E. faecalis isolates from different episodes in the same patient were identical. In a retrospective study, a cohort of patients with monomicrobial (M) EfsB episodes was analyzed. Clinical data from medical records were collected. Furthermore, blood culture isolates from patients with multiple episodes were subjected to whole genome sequencing and multilocus sequence typing. In 666 episodes of MEfsB, 69 patients with IE and 43 with recurrent infections were found. Patients without IE, but with a following episode diagnosed as IE, were compared to those without a following episode. Variables significantly correlated with IE were long duration of symptoms, growth in all blood cultures, unknown origin of infection, heart murmur, and predisposition for IE. Transesophageal echocardiography, all negative, was done in 4 out of 11 episodes during the first episodes, later diagnosed with IE. In 28 of 31 patients with two or more EfsB episodes, isolates with identical sequence type were found. Episodes of EfsB in patients later diagnosed with IE showed features of IE already during the first episodes, were not adequately evaluated, are due to identical isolates, and most likely represent true relapses. Risk factor analysis should guide the use of echocardiography.
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