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Glycodiversification of gentamicins through in vivo glycosyltransferase swapping enabled the creation of novel hybrid aminoglycoside antibiotics with potent activity and low ototoxicity

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Acta Pharmaceutica Sinica B 2024年第9期14卷 4149-4163页

作者： Xinyun Jian Cheng Wang Shijuan Wu Guo Sun Chuan Huang Chengbing Qiu Yuanzheng Liu peter fleadlay Dong Liu Zixin Deng Fuling Zhou Yuhui Sun Department of Hematology Zhongnan Hospital of Wuhan UniversitySchool of Pharmaceutical SciencesWuhan UniversityWuhan 430071China Key Laboratory of Combinatorial Biosynthesis and Drug Discovery(Ministry of Education) Wuhan UniversityWuhan 430071China School of Pharmacy Huazhong University of Science and TechnologyWuhan 430030China School of Life Sciences Co-Innovation Center of NeuroregenerationNantong Laboratory of Development and DiseasesNantong UniversityNantong 226019China Department of Biochemistry University of CambridgeCambridge CB21GAUK Department of Biochemistry and Molecular Biology Biomedicine Discovery InstituteMonash UniversityClayton VIC 3800Australia ARC Centre of Excellence for Innovations in Protein and Peptide Science Monash UniversityClayton VIC 3800Australia

Aminoglycosides(AGs)are a class of antibiotics with a broad spectrum of ***,their use is limited by safety concerns associated with nephrotoxicity and ototoxicity,as well as drug *** address these issues,semi-synthetic approaches for modifying natural AGs have generated new generations of AGs,however,with limited types of modification due to significant challenges in *** study explores a novel approach that harness the bacterial biosynthetic machinery of gentamicins and kanamycins to create hybrid *** was achieved by glycodiversification of gentamicins via swapping the glycosyltransferase(GT)in their producer with the GT from kanamycins biosynthetic pathway and resulted in the creation of a series of novel AGs,therefore referred to as genkamicins(GKs).The manipulation of the hybrid biosynthetic pathway enabled the targeted accumulation of different GK species and the isolation and characterization of six GK *** compounds display retained antimicrobial activity against a panel of World Health Organization(WHO)critical priority pathogens,and GK-C2a,in particular,demonstrates low ototoxicity compared to clinical drugs in zebrafish *** study provides a new strategy for diversifying the structure of AGs and a potential avenue for developing less toxic AG drugs to combat infectious diseases.

关键词： Antibiotic Aminoglycoside biosynthesis Biosynthetic engineering Ototoxicity

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