细菌耐药成为全球性的严重公共卫生问题，国内的耐药形势更为严峻。碱性多肽类药物多粘菌素（B和E）对多药耐药性G-菌具有非常强的抑制活性，但是由于其肾毒性风险的不可控，临床使用受到限制。传统观念认为，多粘菌素类药物在生理条件下带正电荷的氨基是其发挥抗菌作用的关键，同时也是肾毒性产生的重要原因，即正性电荷越多抗菌活性越强，同时肾毒性也越强。课题前期研究中，首次对天然碱性多肽类化合物的单一组分进行了系统的合成制备、生物活性测定及构效与构毒关系分析，发现降低特定位点氨基酸的疏水性，可以在提高抗菌活性的同时降低肾毒性，该发现为以前不曾知晓的新的构效和构毒关系。本课题将在前期研究发现的基础上，首次采用降低碱性氨基酸数（正电荷中心数）与降低特定位点氨基酸的疏水性相结合的策略，设计合成新型低电荷低毒性高活性的碱性多肽抗菌化合物，实现在提高抗菌活性的同时降低肾脏毒性，为治疗临床耐药菌感染提供新的候选药物。

Bacterial resistance has already become a world-wide public health issue, which is particularly serious in China. The polymyxin B and E of polypeptide antibiotics are effective treatment options for Gram-negative resistant bacteria, but their use in clinical practice were waned because of the nephrotoxicity. The positively charged Dab residues of polymyxins are important for antimicrobial activity and will induce nephrotoxicity. In the early study, we synthesized and evaluated the activity of 26 individual components of polymyxins, and summarized their structure-activity relationship and structure-toxicity relationship. We found that the activity will be increased and the nephrotoxicity will be decreased by reducing the hydrophobic property of specific amino acids for the first time. Thus, we will cut down the number of positively charged Dab residues and reduce the hydrophobic property of specific amino acids to synthesize a new type of low alkalinity, low toxicity, and high activity alkaline peptides. New drug candidates with higher antimicrobial potency and lower toxicity may be found based on the foundation of our previous study.