{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "Yantai University , , , ,",
    "Bohai Rim Advanced Research Institute for Drug Discovery , , , ,",
    "Army Medical University , , ,",
    "Shanghai Institute of Materia Medica, Chinese Academy of Sciences , No. 555 Zuchongzhi Road , Pudong, ,",
    "University of Chinese Academy of Sciences , 19 Yuquan Road , ,",
    "Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences , , West 7th Avenue No. 32 , ,"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 11,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Xinru Xia"
    },
    {
      "affs": [
        2
      ],
      "name": "Zhifu Chen"
    },
    {
      "affs": [
        1,
        3,
        4
      ],
      "name": "Yuancun Gu"
    },
    {
      "affs": [
        1
      ],
      "name": "Yi Li"
    },
    {
      "affs": [
        5,
        4
      ],
      "name": "Xingkun Li"
    },
    {
      "affs": [
        1
      ],
      "name": "Xiao He"
    },
    {
      "affs": [
        1,
        3,
        4
      ],
      "name": "Yongxu Zhao"
    },
    {
      "affs": [
        5,
        4
      ],
      "name": "Min Xu",
      "orcid": "0000-0002-6661-5177"
    },
    {
      "affs": [
        1
      ],
      "name": "Fang Li"
    },
    {
      "affs": [
        2
      ],
      "name": "Jinyong Zhang"
    },
    {
      "affs": [
        0,
        1,
        3,
        4
      ],
      "name": "Dongliang Guan",
      "orcid": "0000-0002-7814-1116"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/4b0pafvkbshzt.bib",
  "cited_by": 0,
  "doi": "10.1021/jacsau.6c01427",
  "fulltext_url": null,
  "id": "4b0pafvkbshzt",
  "issns": [
    "2691-3704"
  ],
  "landing_url": "https://pubs.acs.org/jaaucr/article/doi/10.1021/jacsau.6c01427/5461182/Reprogramming-the-Kyn-13-Locus-of-Daptomycin",
  "language": null,
  "licence": "CC-BY-NC-ND-4.0",
  "licence_label": "CC BY-NC-ND 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [],
  "openalex": null,
  "pdf_url": "https://pubs.acs.org/doi/pdf/10.1021/jacsau.6c01427",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-29",
  "publisher": "American Chemical Society (ACS)",
  "ris": "https://research.draconitic.com/paper/4b0pafvkbshzt.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:18:36Z",
      "native_id": "10.1021/jacsau.6c01427",
      "source": "crossref",
      "url": "https://pubs.acs.org/jaaucr/article/doi/10.1021/jacsau.6c01427/5461182/Reprogramming-the-Kyn-13-Locus-of-Daptomycin"
    }
  ],
  "subjects": [
    {
      "field": "chemistry",
      "origin": "issn:2691-3704",
      "subfield": "general"
    }
  ],
  "title": "Reprogramming the Kyn-13 Locus of Daptomycin Unlocks a Serendipitous Theranostic Paradigm",
  "title_text": "Reprogramming the Kyn-13 Locus of Daptomycin Unlocks a Serendipitous Theranostic Paradigm",
  "type": "peer-reviewed",
  "updated_at": "2026-10-31T00:20:48Z",
  "url": "https://research.draconitic.com/paper/4b0pafvkbshzt",
  "venue": "JACS Au",
  "versions": []
}