细菌耐药性的产生已成为威胁人类健康的严重问题，如何有效控制多耐药革兰氏阴性菌感染更是当前人类面临的巨大挑战。双环霉素是一个具有中等抑制革兰氏阴性菌的“老药”，我们的前期工作表明:当双环霉素与抑制RNA转录或蛋白质合成的抑菌抗生素联用时，双环霉素会对多种细菌从简单抑菌变成高效杀菌。运用“老药新用”的策略，本课题拟开展基于双环霉素的治疗多耐药革兰氏阴性菌的机制和应用研究。具体包括以下方面： 1）双环霉素联合用药治疗多耐药革兰氏阴性菌的体内药效评价；2）双环霉素的生物合成研究；3）双环霉素联合用药的分子机制研究。因此，该课题从三个层次入手，既有理论上的重要性，也有很强的应用价值。协同杀菌作用将双环霉素从抑菌剂提升为杀菌剂，为更快、更好地控制感染，预防新耐药的产生开辟了新思路。

Antibiotics have saved millions of lives from infectious diseases, and they have enabled many medical procedures to be performed with little risk of post-procedure infection. However, misuse of antimicrobials has allowed bacterial resistance to threaten much of modern medicine. Among the most notorious pathogens are Gram-negative bacteria that have acquired resistance to multiple, or even all, currently available antimicrobials..Here, we seek to expand the utility of the antibiotic bicyclomycin (BCM) for the treatment of multi-drug-resistant (MDR) Gram-negative infections. It was recently shown that BCM exhibits lethal synergy towards clinically important pathogens when co-administered with known RNA/protein synthesis inhibitors. In the absence of a gene synthesis inhibitor, BCM induces the expression of a factor that protects the cell from BCM bactericidal activity. The novel killing activity of BCM may lead to novel regimens for MDR Gram-negative bacterial infections, so we propose to investigate its potential via three interrelated multidisciplinary aims:.(1) To validate BCM-mediated lethal synergy in animal infection models by showing that the lethal combination rapidly cures infection and severely restricts the emergence of resistance..(2) To elucidate the BCM biosynthetic pathway with the goal of engineering high-yield Streptomyces strains and producing novel BCM derivatives by combining biosynthetic engineering with synthetic chemistry..(3) To identify and characterise the protein that protects bacteria from being killed by BCM via proteomic, biochemical, and structural studies, with the ultimate goal of developing a small-molecule inhibitor of this protein to promote BCM lethality.