Bellucci Maria Cristina, Romani Carola, Sani Monica, Volonterio Alessandro
Department of Food, Environmental, and Nutritional Sciences, Università degli Studi di Milano, Via Celoria 2, 20131 Milano, Italy.
Department of Chemistry, Materials, and Chemical Engineering "Giulio Natta", Politecnico di Milano, Via Mancinelli 7, 20131 Milano, Italy.
Antibiotics (Basel). 2024 Aug 21;13(8):783. doi: 10.3390/antibiotics13080783.
In recent years, bacterial resistance to conventional antibiotics has become a major concern in the medical field. The global misuse of antibiotics in clinics, personal use, and agriculture has accelerated this resistance, making infections increasingly difficult to treat and rendering new antibiotics ineffective more quickly. Finding new antibiotics is challenging due to the complexity of bacterial mechanisms, high costs and low financial incentives for the development of new molecular scaffolds, and stringent regulatory requirements. Additionally, innovation has slowed, with many new antibiotics being modifications of existing drugs rather than entirely new classes. Antimicrobial peptides (AMPs) are a valid alternative to small-molecule antibiotics offering several advantages, including broad-spectrum activity and a lower likelihood of inducing resistance due to their multifaceted mechanisms of action. However, AMPs face challenges such as stability issues in physiological conditions, potential toxicity to human cells, high production costs, and difficulties in large-scale manufacturing. A reliable strategy to overcome the drawbacks associated with the use of small-molecule antibiotics and AMPs is combination therapy, namely the simultaneous co-administration of two or more antibiotics or the synthesis of covalently linked conjugates. This review aims to provide a comprehensive overview of the literature on the development of antibiotic-AMP conjugates, with a particular emphasis on critically analyzing the design and synthetic strategies employed in their creation. In addition to the synthesis, the review will also explore the reported antibacterial activity of these conjugates and, where available, examine any data concerning their cytotoxicity.
近年来，细菌对传统抗生素的耐药性已成为医学领域的一个主要问题。全球范围内，临床、个人使用及农业中抗生素的滥用加速了这种耐药性，使得感染越来越难以治疗，新抗生素也更快失效。由于细菌机制的复杂性、开发新分子骨架的高成本和低经济激励以及严格的监管要求，寻找新抗生素具有挑战性。此外，创新速度放缓，许多新抗生素都是现有药物的修饰，而非全新的类别。抗菌肽（AMPs）是小分子抗生素的有效替代品，具有多种优势，包括广谱活性以及由于其多方面的作用机制而产生耐药性的可能性较低。然而，抗菌肽面临诸多挑战，如在生理条件下的稳定性问题、对人体细胞的潜在毒性、高生产成本以及大规模生产的困难。克服与使用小分子抗生素和抗菌肽相关缺点的一个可靠策略是联合疗法，即同时共同施用两种或更多种抗生素或合成共价连接的缀合物。本综述旨在全面概述有关抗生素 - 抗菌肽缀合物开发的文献，特别着重于批判性地分析其制备过程中所采用的设计和合成策略。除了合成方面，该综述还将探讨这些缀合物已报道的抗菌活性，并在可行的情况下，研究有关其细胞毒性的任何数据。
