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

Xinyun Jian; Cheng Wang; Shijuan Wu; Guo Sun; Chuan Huang; Chengbing Qiu; Yuanzheng Liu; Peter F Leadlay; Dong Liu; Zixin Deng; Fuling Zhou; Yuhui Sun

doi:10.1016/j.apsb.2024.04.030

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

Acta Pharm Sin B. 2024 Sep;14(9):4149-4163. doi: 10.1016/j.apsb.2024.04.030. Epub 2024 May 3.

Authors

Xinyun Jian^{1

2

3

4}, Cheng Wang⁵, Shijuan Wu^{1

2}, Guo Sun^{1

2}, Chuan Huang^{1

2}, Chengbing Qiu^{1

2}, Yuanzheng Liu^{1

2}, Peter F Leadlay⁶, Dong Liu⁵, Zixin Deng^{1

2}, Fuling Zhou¹, Yuhui Sun^{1

2

7}

Affiliations

¹ Department of Hematology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China.
² Key Laboratory of Combinatorial Biosynthesis and Drug Discovery (Ministry of Education), Wuhan University, Wuhan 430071, China.
³ Department of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Monash University, Clayton VIC 3800, Australia.
⁴ ARC Centre of Excellence for Innovations in Protein and Peptide Science, Monash University, Clayton VIC 3800, Australia.
⁵ School of Life Sciences, Co-Innovation Center of Neuroregeneration, Nantong Laboratory of Development and Diseases, Nantong University, Nantong 226019, China.
⁶ Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, UK.
⁷ School of Pharmacy, Huazhong University of Science and Technology, Wuhan 430030, China.

Abstract

Aminoglycosides (AGs) are a class of antibiotics with a broad spectrum of activity. However, their use is limited by safety concerns associated with nephrotoxicity and ototoxicity, as well as drug resistance. To 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 synthesis. This study explores a novel approach that harness the bacterial biosynthetic machinery of gentamicins and kanamycins to create hybrid AGs. This 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 components. These 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 embryos. This 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.

Keywords: Aminoglycoside biosynthesis; Antibiotic; Biosynthetic engineering; Ototoxicity.