A facile and selective derivatization approach on kynurenine-NH2 in daptomycin, leading to the discovery of hexakynomycin to combat multidrug-resistant Gram-positive pathogens especially daptomycin-resistant bacteria

Dongliang Guan; Jian Li; Feifei Chen; Jiaqi Li; Xiaolei Bian; Yue Yu; Xinxin Feng; Lefu Lan; Wei Huang

doi:10.1016/j.ejmech.2023.115638

A facile and selective derivatization approach on kynurenine-NH₂ in daptomycin, leading to the discovery of hexakynomycin to combat multidrug-resistant Gram-positive pathogens especially daptomycin-resistant bacteria

Eur J Med Chem. 2023 Nov 5:259:115638. doi: 10.1016/j.ejmech.2023.115638. Epub 2023 Jul 20.

Authors

Dongliang Guan¹, Jian Li², Feifei Chen², Jiaqi Li³, Xiaolei Bian⁴, Yue Yu³, Xinxin Feng⁵, Lefu Lan⁶, Wei Huang⁷

Affiliations

¹ State Key Laboratory of Drug Research, Center for Biotherapeutics Discovery Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No.555 Zuchongzhi Rd, Pudong, Shanghai, 201203, China; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong, 264117, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China. Electronic address: dlguan@baridd.ac.cn.
² State Key Laboratory of Drug Research, Center for Biotherapeutics Discovery Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No.555 Zuchongzhi Rd, Pudong, Shanghai, 201203, China; School of Pharmaceutical Science and Technology, Hangzhou Institute of Advanced Study, Hangzhou, 310024, China.
³ State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan Provincial Key Laboratory of Biomacromolecular Chemical Biology, and School of Chemistry and Chemical Engineering, Hunan University, Changsha, Hunan, 410082, China.
⁴ Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong, 264117, China.
⁵ State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan Provincial Key Laboratory of Biomacromolecular Chemical Biology, and School of Chemistry and Chemical Engineering, Hunan University, Changsha, Hunan, 410082, China. Electronic address: xinxin_feng@hnu.edu.cn.
⁶ School of Pharmaceutical Science and Technology, Hangzhou Institute of Advanced Study, Hangzhou, 310024, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China. Electronic address: llan@ucas.ac.cn.
⁷ State Key Laboratory of Drug Research, Center for Biotherapeutics Discovery Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No.555 Zuchongzhi Rd, Pudong, Shanghai, 201203, China; School of Pharmaceutical Science and Technology, Hangzhou Institute of Advanced Study, Hangzhou, 310024, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing, 100049, China. Electronic address: huangwei@simm.ac.cn.

PMID: 37482019
DOI: 10.1016/j.ejmech.2023.115638

Abstract

Wide-spread use of daptomycin unavoidably resulted in the emergence of daptomycin-resistant pathogens. In the hunt for more active daptomycin derivatives through medicinal chemistry studies, we established a concise semisynthetic approach to modify the L-Kyn13 on daptomycin specifically and effectively. Here, 19 novel derivatives with certain diversity were designed and synthesized to perform a comprehensive SAR study on this underestimated position. The optimal compound, termed "hexakynomycin", as the new generation of daptomycin-based antibiotic candidate exhibited 4->125-fold higher activity against methicillin-susceptible S. aureus (MSSA), methicillin-resistant S. aureus (MRSA), vancomycin-intermediate resistant S. aureus (VISA), and vancomycin-resistant Enterococci (VRE), including daptomycin-resistant strains, compared with that of daptomycin. Greater membrane binding capacity rendered hexakynomycin better activity and special antibiotic property. Hexakynomycin also demonstrated a better pharmacokinetic profile, good safety features and good pharmacodynamics properties. This work provided an effective modification strategy aiming at daptomycin which provided significant insights and showed great promise for the next generation of daptomycin derivatives.

Keywords: Daptomycin derivatives; Hexakynomycin; Kynurenine; Lipopeptide; Multidrug-resistant bacteria.

MeSH terms

Anti-Bacterial Agents / pharmacology
Anti-Bacterial Agents / therapeutic use
Daptomycin* / pharmacology
Kynurenine
Methicillin-Resistant Staphylococcus aureus*
Microbial Sensitivity Tests
Staphylococcus aureus

Substances

Daptomycin
Kynurenine
Anti-Bacterial Agents