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Bio-Inspired Glycan-NanoProbes as Antimicrobial Pro-Drugs

Periodic Reporting for period 1 - BioNanoProbes (Bio-Inspired Glycan-NanoProbes as Antimicrobial Pro-Drugs)

Reporting period: 2019-05-01 to 2021-04-30

Antimicrobial resistance (AMR) is a recognized global challenge. Tools for bacterial detection can combat AMR by facilitating evidence-based antibiotic prescribing, thus avoiding empirical use that can contribute to the spread of resistance. Unfortunately, traditional culture-based identification methods take at least a day, while emerging alternatives are limited by high cost and requirement for skilled operators. The proposal “Bio-inspired glycan-nanoprobes as antimicrobial prodrugs” (BioNanoProbes) has evaluated glycan-CDots as tools for rapid detection of specific bacteria, establishing their viability, together with the quantum photonic sensor (QPS) detection developed by our industrial partner Fluoretiq, as the basis for a rapid diagnostic method. There is no doubt that success in this endeavour can have a major impact in organic synthesis, glycobiology, molecular medicine and drug discovery.
Owing to the urgent for novel antimicrobials that target specific bacterial populations, objectives of this Marie Sklodowska Curie Action (MSCA) have been to develop of new chemical tools that can be used to label bacteria and/or delivery of antimicrobial drugs. The novelty of this approach lies not only in the synthetic schemes, but also in the approach and their potential biological applications of the proposed bio-inspired glyco-nanoprobes as antimicrobial pro-drugs.
In summary, the proposed work represents an ambitious and wide ranging multi- and interdisciplinary research programme aimed at developing the next generation of antimicrobials to overcome antibiotic resistance.
We have synthetized a series of biological relevant O-glycans, known to be key binders to specific bacterial surfaces, as well as their corresponding glycodendrons ready to be conjugated to water soluble fluorescent and multifunctional CDots. The synthetic schemes used to obtain the glycan structures, CDots and glyco-CDots are all novels. New technology has been developed to control density and distribution of surface glycans on CDots as well as multifunctionality (e.g. glycan or glycan combinations as well as glycan/drug conjugates) to enhance particle bioavailability, stability and targeting ability for specific biological studies (e.g. lectin binding as well as bacteria targeting). Studies of cell internalization and localization of the novel glycan-nanoprobes and analysis of their cytotoxicity mechanisms as well as their uptake mechanism has been carried out within the proposed work. After selecting the optimal glycan- or glycan/drug-nanodot combinations, we have validated our glycan-based targeted drug delivery systems (Smart Glyco-CDots) using traditional antibiotics known for their ability to target bacteria, but that have become less effective against resistant strains (e.g. oxazolidinones). The novel glycan/drug-CDots using combinations of specific glycans/antibotics has been evaluated for their ability to selectively deliver the drug to specific bacteria in bacterial binding and killing assays (against a range of clinically relevant bacterial pathogens e.g. E. coli; S. aureus, P. aeruginosa) and screened for selective labelling and drug release. This work has been carried out in collaboration with Dr. J. Spencer (School of Cellullar and Molecular Medicine, Bristol) and FluoretiQ (Quantum enhaced fluoresce sensor specifically for our CDots).
The final results derived from the implementation of this action could be disseminated at two different levels: 1) via publication in international scientific journals: leading scientific multidisciplinary journals such Science, Nature (including its specific Nature sister journals), or chemistry journals such as ACIE, JACS or Chem. Sci., depending on the novelty of the discovery. In accordance with the principles of H2020, results will be published in open access whenever possible; and 2) the results could also be disseminated to industrial partners. In this context, potential intellectual property arising from BioNanoProbes could be evaluated and managed by the Technology Transfer Unit of University of Bristol. The research results could be disclosed to potentially interested industrial contacts in the context of non-disclosure agreements, and the possibilities for collaboration with additional industrial funding, and for licensing could be explored. This project could significantly streamline the synthesis of new bio-inspired glyco-nanoprobes as diagnostic tools and antimicrobial pro-drugs, and thus, it is likely that important industrial applications will result. The data sets collected during this MSCA will inform and enhance dozens of publications in the coming years.
Harnessing chemical technologies effectively, sustainably for drug development for life-threatening diseases are the key element for achieving EU sustainable development. This project introduces an efficient methodology for the development of a targeted delivery system using glycan derivatives as probes for labelling of, and the delivery of antibiotics into, bacteria with the ultimate goal of developing antimicrobial therapies. This will contribute to ensuring the EU sustainable future. The glycan-based drug delivery systems detailed in this action will make a significant contribution to Europe’s world research standing and advance knowledge for the research community, business and society.