Development of new antimicrobial agents based on natural products

Proposal by Dr Patricia Ragazzon, School of Environment & Life Sciences

Introduction: Microbial origin infections are a major cause of disability, morbidity and mortality around the world and especially in developing countries. Easy access to antimicrobials has led to inappropriate use of antibiotics as well as high-intensity food production, leading to bacteria becoming resistant to current antibiotics. The resulting “super-bugs” are becoming a worldwide threat, as known antibiotics are non-effective and many of the currently under development agents have terrible side effects.

Objectives: The aim of this project is to produce a new generation of anti-bacterial/anti-fungal agents with minimum side effects and active against antibiotic resistant strains that are proving difficult to treat. Many compounds with antimicrobial properties bind to DNA by intercalating the base pairs. These compounds stabilise the double helical structure interrupting the transcription and replication of the DNA in the dividing cell. Different types of DNA structures can be found in living organisms, the most common is the duplex DNA form, recent evidence shows guanine rich nucleic acids can form sequence dependant higher structures called quadruplexes that are composed of four strands of nucleic acids. Computational biology analysis and indirect biological studies have demonstrated that these higher structures could be present in several genomes, being responsible for many transcription processes.

Approach: In recent years research has focused on studying the antimicrobial activity of flavonoids with very encouraging results as many of these flavonoids have shown to be active against different strains of Salmonella, Escherichia, Staphylococcus and Streptococcus. Interaction of flavonoids with nucleic acids occurs based on the planar flavonoid structure intercalating with the bases. The project involves the synthesis of a new generation of compounds based on the formation of bis-flavonoids by linking two mono-flavonoids. These bis-flavonoids will be modified on both the linker lengths and ring substitutions to optimise the interaction and preference for pathogenic duplex and quadruplex DNA as a way of exerting their therapeutic activity. We will then study the activity against several genomic nucleic acid sequences by biophysical and biological techniques. With the in vitro data obtained, we will produce structure activity related studies (SARS) allowing us to rationally design an improved family of compounds, which will be further tested for antimicrobial activity in several organisms.

For further information please contact: p.a.ragazzon@salford.ac.uk

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