Reprogramming the Kyn-13 Locus of Daptomycin Unlocks a Serendipitous Theranostic Paradigm
6 affiliations
- 1Yantai University , , , ,
- 2Bohai Rim Advanced Research Institute for Drug Discovery , , , ,
- 3Army Medical University , , ,
- 4Shanghai Institute of Materia Medica, Chinese Academy of Sciences , No. 555 Zuchongzhi Road , Pudong, ,
- 5University of Chinese Academy of Sciences , 19 Yuquan Road , ,
- 6Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences , , West 7th Avenue No. 32 , ,
Abstract
Driven by the escalating multidrug-resistant superbug crisis (e.g., methicillin- and vancomycin-resistant strains) and the sparse clinical lipopeptide pipeline, we designed and synthesized 36 daptomycin derivatives, termed “kynurarylmycins”, based on the facile regiospecific reductive amination approach at the Kyn-13 site of daptomycin with diverse aromatic aldehydes. Systematic SAR analysis revealed Kyn-13 arylation as a highly effective strategy to boost antibacterial potency. The lead candidate Dap-34 exhibits outstanding broad-spectrum activity against high-priority Gram-positive pathogens, including clinical isolates, outperforming daptomycin and vancomycin by 32- and 512-fold, respectively. Mechanistically, Dap-34 disrupts cell envelope activity via two independent pathways: it induces faster and stronger membrane depolarization with mild permeabilization to disrupt membrane homeostasis, and augments inhibition of cell wall biosynthesis. This dual-targeted lethality translates into superior in vivo therapeutic efficacy in murine infection models. Serendipitously, this modification remodels daptomycin′s intrinsic photophysics, triggering marked fluorescence turn-on in bacterial lipid microenvironments for high-contrast, wash-free, label-free live imaging. This work redefines Kyn-13 as a dual pharmacological and photophysical hub, offering an unprecedented theranostic paradigm for combating antimicrobial resistance.
Related
- Serendipitous crystal structure of mJuniper, a rationally designed cyan fluorescent protein
- From Targeted Synthesis to Serendipitous Discovery: Transforming Perfluorotoluene into Discotic Liquid Crystals and Dearomatized Spirofluorenes
- Cell-derived biomimetic nanomedicines: Emerging theranostic platforms for precision management of atherosclerosis.
- Tailoring Chain-Edge C=R (R = C, O, S) Microenvironments in sp2-Carbon-Bridged 1D COFs Unlocks a ‘Moderate Balance’ Effect for Photocatalytic H2O2 Production
- Hybrid Nanocrystalline Theranostic Agents Designed for Magnetic Resonance Imaging, Photothermal, and Photodynamic Therapies Against Cancer
BibTeX
@article{xia2026reprogramming,
title = {{Reprogramming the Kyn-13 Locus of Daptomycin Unlocks a Serendipitous Theranostic Paradigm}},
author = {Xinru Xia and Zhifu Chen and Yuancun Gu and Yi Li and Xingkun Li and Xiao He and Yongxu Zhao and Min Xu and Fang Li and Jinyong Zhang and Dongliang Guan},
journal = {JACS Au},
year = {2026},
month = oct,
doi = {10.1021/jacsau.6c01427},
url = {https://pubs.acs.org/jaaucr/article/doi/10.1021/jacsau.6c01427/5461182/Reprogramming-the-Kyn-13-Locus-of-Daptomycin},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Reprogramming the Kyn-13 Locus of Daptomycin Unlocks a Serendipitous Theranostic Paradigm
AU - Xinru Xia
AU - Zhifu Chen
AU - Yuancun Gu
AU - Yi Li
AU - Xingkun Li
AU - Xiao He
AU - Yongxu Zhao
AU - Min Xu
AU - Fang Li
AU - Jinyong Zhang
AU - Dongliang Guan
PY - 2026
DA - 2026/10/29
JO - JACS Au
DO - 10.1021/jacsau.6c01427
UR - https://pubs.acs.org/jaaucr/article/doi/10.1021/jacsau.6c01427/5461182/Reprogramming-the-Kyn-13-Locus-of-Daptomycin
AB - Driven by the escalating multidrug-resistant superbug crisis (e.g., methicillin- and vancomycin-resistant strains) and the sparse clinical lipopeptide pipeline, we designed and synthesized 36 daptomycin derivatives, termed “kynurarylmycins”, based on the facile regiospecific reductive amination approach at the Kyn-13 site of daptomycin with diverse aromatic aldehydes. Systematic SAR analysis revealed Kyn-13 arylation as a highly effective strategy to boost antibacterial potency. The lead candidate Dap-34 exhibits outstanding broad-spectrum activity against high-priority Gram-positive pathogens, including clinical isolates, outperforming daptomycin and vancomycin by 32- and 512-fold, respectively. Mechanistically, Dap-34 disrupts cell envelope activity via two independent pathways: it induces faster and stronger membrane depolarization with mild permeabilization to disrupt membrane homeostasis, and augments inhibition of cell wall biosynthesis. This dual-targeted lethality translates into superior in vivo therapeutic efficacy in murine infection models. Serendipitously, this modification remodels daptomycin′s intrinsic photophysics, triggering marked fluorescence turn-on in bacterial lipid microenvironments for high-contrast, wash-free, label-free live imaging. This work redefines Kyn-13 as a dual pharmacological and photophysical hub, offering an unprecedented theranostic paradigm for combating antimicrobial resistance.
SN - 2691-3704
ER -