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BIT Has Made Achievements in the Study of Antibiotic with Hybrid Dual Modes of Action

release date :2020-05-08 02:33:00  |   [ close window ]ViewCount:

  Beijing Institute of Technology, Apr 15th, 2020:  Recently, Liang Jianhua’s research group of School of Chemistry and Chemical Engineering in Beijing Institute of Technology fused azithromycin and quinolone and obtained the first macrolide hybrid antibiotic with dual action modes of ribosome and topoisomerase. The research results titled “Design, synthesis and structure-activity relationships of novel 15-membered macrolides: Quinolone/quinoline-containing sidechains tethered to the C-6 position of azithromycin acylides” was published on top medical journal European Journal of Medicinal Chemistry, which links to

  Drug-resistant bacteria infection has become one of the worldwide major threats to human health. But now antibiotics face the R & D dilemma that once they are launched, antibiotic resistance emerges quickly.  Macrolide antimicrobial has an affinity for the nascent peptide channels of bacterial ribosomes, which hinders protein export.  Quinolone acts on topoisomerase, formed topoisomerase-drug-DNA ternary complex would lead to inhibition of DNA replication.  Based on the theory of hybrid antibiotics, two molecules with different mechanisms of action are covalently linked to obtain a hybrid with a dual modes of action to overcome the resistance mechanism of one or two drugs ,regain antibacterial activity and significantly reduce the probability of microbial resistance. The difficulty of this study is that the ribosome and topoisomerase are two very different targets, and the structural requirements of the ligands are quite different, consequently make it difficult for the hybrid to achieve the two targets simultaneously. Liang Jianhua’s research group took azithromycin as the lead and bound the quinolone compounds to the C-6 position of azithromycin by acylation, after screening, it was found that hybrids of azithromycin and ciprofloxacin / gatifloxacin can inhibit the replication of bacterial DNA in a manner similar to fluoroquinolone-poisoning gyrase, thereby improving the compound's antibacterial activity against high-level resistant bacteria.  The research used studies like DNA supercoiling assay, DNA cleavage assay, molecular docking study and whole cell level growth inhibition study to verify, the results are consistent. The dual modes of action that can inhibit both protein synthesis and DNA replication has laid the foundation for the rational design of new antibiotics against drug-resistant bacteria in the future.

       The first author of the work is Fan Bingzhi, a master student from School of Chemistry and Chemical Engineering of BIT. The corresponding author is Liang Jianhua, associate professor from School of Chemistry and Chemical Engineering of BIT. Professor Hiasa from University of Minnesota Medical School, professor Aldrich from University of Minnesota Pharmacy School and professor Cushman from the Purdue College of Pharmacy also participated in this research.  The research has received long-term support from projects such as National Natural Science Foundation of China (20602002; 81673335), Outstanding Talents from Beijing (2013D009011000002) and Excellent Young Teachers from BIT (2012YG1606).

  Attached personal profile:
Associate professor Liang Jianhua, 1995-2004 in BIT, bachelor/doctor. From 2004 he works as Lecturer / Associate Professor / PhD Supervisor in BIT. His research direction is Medicinal Chemistry, which indicates in the development of related innovative drugs for the treatment of various major diseases. His research interests include anti-resistant bacteria, anti-viral infection drugs, anti-neurodegenerative drugs, anti-diabetic drugs, etc. He is now in charge of two projects of the National Natural Science Foundation of China, projects of National Key R&D Program of China, etc. Up to now, he has published more than 20 papers in such academic journals as Eur. J. Med. Chem.、Bioorg. & Med. Chem.、Bioorg. & Med. Chem. Lett.、Curr. Top. Med. Chem.、J. Antibiotics, owns 7 first inventor authorized patents and 3 PCT patents.


News Source: School of Chemistry and Chemical Engineering
Translator: Huang Mingyu,News Agency of BIT
Editor: News Agency of BIT

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