New approaches for the design and synthesis of heterocyclic and macrocyclic bioactive peptidomimetics

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With the worldwide increase of microbial resistance to antibiotics, the prevention and treatment of bacterial infections have become challenging not only in human health but also in veterinary medicine and animal husbandry. The control of bacterial growth is also a major concern in the food industry where foodborne illness outbreaks can cause human deaths and be very expensive and damaging for businesses. In this context, new highly effective antimicrobial agents are crucially needed in food safety, animal husbandry, veterinary medicine and human health. To accelerate the discovery of new antimicrobial agents, the design of compounds that target hitherto unexploited bacterial machineries and the access to molecular scaffolds capable of functional and structural modifications have become essential. Among the most promising strategies and scaffolds, we are particularly interested in heterocycles and antimicrobial peptides. This research proposal describes novel approaches to access engineerable molecular scaffolds for bacterial protein binding and manipulation and the development of innovative antimicrobial agents. The first part describes the development of synthetic methodologies to prepare benzo-fused heterocyclic scaffolds with abilities to mimic protein secondary structures. The proposed approach uses a multicomponent reaction to prepare polysubstituted heterocycles with different ring sizes and substitution patterns. With its great potential and flexibility, the proposed approach will give access to a wide array of functionalized benzo-fused heterocyclic compounds. The second part involves the design and development of mimetic approaches to exploit the attractive structural behaviour and mode of action of antimicrobial peptides from the microcin family. These antimicrobial peptides are among the most promising alternatives to conventional but their use is often limited by low production yields. In a first project, macrocyclic peptides will be designed and synthesized to mimic the lasso topology of microcin J25 and give access to this promising structure. Some microcins contain an iron-chelating unit, called siderophore, and can highjack the bacterial iron-transport system to reach their target and kill bacteria. Inspired by this strategy, the second project involves the addition of siderophores to antimicrobial peptides to increase potency and expend their spectra of activity. The development of new antimicrobials is a challenging and important goal in fundamental and applied research. The developed of synthetic approaches will unfold new possibilities to reach novel and complex molecular structures. Our work will give access to new approaches and molecular scaffolds for peptide mimicry. The proposed research program will have a strong impact in organic and medicinal chemistry as well as food, veterinary and medical microbiology since antimicrobials are used in food safety, animal production, human health and veterinary medicine.