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

随着世界范围内微生物对抗生素耐药性的增加，细菌感染的预防和治疗不仅对人类健康构成挑战，而且在兽医和畜牧业也是如此。细菌生长的控制也是食品业的一个主要问题，食源性疾病的爆发可能导致人类死亡，对企业来说代价非常高昂，并具有破坏性。在这种背景下，在食品安全、畜牧业、兽医和人类健康方面迫切需要新的高效抗菌剂。为了加速发现新的抗菌剂，针对迄今尚未开发的细菌机制的化合物的设计以及能够进行功能和结构修饰的分子支架的获得变得至关重要。在最有前景的策略和支架中，我们对杂环和抗菌肽特别感兴趣。这项研究计划描述了用于细菌蛋白结合和操作的可工程分子支架的新方法，以及创新抗菌剂的开发。第一部分介绍了合成方法的发展，以制备具有模拟蛋白质二级结构能力的苯并稠合杂环支架。该方法利用多组分反应合成具有不同环大小和取代方式的多取代杂环。由于其巨大的潜力和灵活性，所提出的方法将使人们有可能获得一系列功能化的苯并稠杂环化合物。第二部分涉及设计和开发模拟方法，以开发来自微霉素家族的抗菌肽吸引人的结构行为和作用模式。这些抗菌肽是传统抗菌肽最有希望的替代品之一，但它们的使用往往受到产量低的限制。在第一个项目中，将设计和合成大环肽来模拟microCin J25的套索拓扑结构，并获得这一有希望的结构。一些微球蛋白含有一种称为铁载体的铁螯合单元，可以劫持细菌的铁运输系统，从而到达它们的目标位置并杀死细菌。在这一战略的启发下，第二个项目涉及在抗菌肽中添加铁载体，以提高效力并扩大其活性光谱。新型抗菌药物的开发是基础研究和应用研究中具有挑战性和重要意义的目标。合成方法的发展将为获得新颖和复杂的分子结构提供新的可能性。我们的工作将为多肽模拟提供新的方法和分子支架。由于抗菌剂用于食品安全、动物生产、人类健康和兽医医学，拟议的研究计划将对有机和药物化学以及食品、兽医和医学微生物学产生重大影响。

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.