IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-50453-3.html
   My bibliography  Save this article

A synthetic antibiotic class with a deeply-optimized design for overcoming bacterial resistance

Author

Listed:
  • Jin Feng

    (Huazhong Agricultural University)

  • Youle Zheng

    (Huazhong Agricultural University)

  • Wanqing Ma

    (Huazhong Agricultural University)

  • Defeng Weng

    (Huazhong Agricultural University)

  • Dapeng Peng

    (Huazhong Agricultural University
    Huazhong Agricultural University)

  • Yindi Xu

    (Henan Academy of Agricultural Sciences)

  • Zhifang Wang

    (Henan Academy of Agricultural Sciences)

  • Xu Wang

    (Huazhong Agricultural University
    Huazhong Agricultural University)

Abstract

The lack of new drugs that are effective against antibiotic-resistant bacteria has caused increasing concern in global public health. Based on this study, we report development of a modified antimicrobial drug through structure-based drug design (SBDD) and modular synthesis. The optimal modified compound, F8, was identified, which demonstrated in vitro and in vivo broad-spectrum antibacterial activity against drug-resistant bacteria and effectively mitigated the development of resistance. F8 exhibits significant bactericidal activity against bacteria resistant to antibiotics such as methicillin, polymyxin B, florfenicol (FLO), doxycycline, ampicillin and sulfamethoxazole. In a mouse model of drug-resistant bacteremia, F8 was found to increase survival and significantly reduce bacterial load in infected mice. Multi-omics analysis (transcriptomics, proteomics, and metabolomics) have indicated that ornithine carbamoyl transferase (arcB) is a antimicrobial target of F8. Further molecular docking, Isothermal Titration Calorimetry (ITC), and Differential Scanning Fluorimetry (DSF) studies verified arcB as a effective target for F8. Finally, mechanistic studies suggest that F8 competitively binds to arcB, disrupting the bacterial cell membrane and inducing a certain degree of oxidative damage. Here, we report F8 as a promising candidate drug for the development of antibiotic formulations to combat antibiotic-resistant bacteria-associated infections.

Suggested Citation

  • Jin Feng & Youle Zheng & Wanqing Ma & Defeng Weng & Dapeng Peng & Yindi Xu & Zhifang Wang & Xu Wang, 2024. "A synthetic antibiotic class with a deeply-optimized design for overcoming bacterial resistance," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50453-3
    DOI: 10.1038/s41467-024-50453-3
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-50453-3
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-024-50453-3?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Christopher Walsh, 2000. "Molecular mechanisms that confer antibacterial drug resistance," Nature, Nature, vol. 406(6797), pages 775-781, August.
    2. Matthew J. Mitcheltree & Amarnath Pisipati & Egor A. Syroegin & Katherine J. Silvestre & Dorota Klepacki & Jeremy D. Mason & Daniel W. Terwilliger & Giambattista Testolin & Aditya R. Pote & Kelvin J. , 2021. "A synthetic antibiotic class overcoming bacterial multidrug resistance," Nature, Nature, vol. 599(7885), pages 507-512, November.
    3. Eric D. Brown & Gerard D. Wright, 2016. "Antibacterial drug discovery in the resistance era," Nature, Nature, vol. 529(7586), pages 336-343, January.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Elsa Hansen & Jason Karslake & Robert J Woods & Andrew F Read & Kevin B Wood, 2020. "Antibiotics can be used to contain drug-resistant bacteria by maintaining sufficiently large sensitive populations," PLOS Biology, Public Library of Science, vol. 18(5), pages 1-20, May.
    2. Takeshi Nakaya & Miyuki Yabe & Ellene H. Mashalidis & Toyotaka Sato & Kazuki Yamamoto & Yuta Hikiji & Akira Katsuyama & Motoko Shinohara & Yusuke Minato & Satoshi Takahashi & Motohiro Horiuchi & Shin-, 2022. "Synthesis of macrocyclic nucleoside antibacterials and their interactions with MraY," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    3. Hajkowicz, Stefan & Naughtin, Claire & Sanderson, Conrad & Schleiger, Emma & Karimi, Sarvnaz & Bratanova, Alexandra & Bednarz, Tomasz, 2022. "Artificial intelligence for science – adoption trends and future development pathways," MPRA Paper 115464, University Library of Munich, Germany.
    4. Chih-Wei Chen & Nadja Leimer & Egor A. Syroegin & Clémence Dunand & Zackery P. Bulman & Kim Lewis & Yury S. Polikanov & Maxim S. Svetlov, 2023. "Structural insights into the mechanism of overcoming Erm-mediated resistance by macrolides acting together with hygromycin-A," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    5. Narayan Prasad Parajuli & Andrew Emmerich & Chandra Sekhar Mandava & Michael Y. Pavlov & Suparna Sanyal, 2023. "Antibiotic thermorubin tethers ribosomal subunits and impedes A-site interactions to perturb protein synthesis in bacteria," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    6. Xueqin Shu & Yingying Shi & Yi Huang & Dan Yu & Baolin Sun, 2023. "Transcription tuned by S-nitrosylation underlies a mechanism for Staphylococcus aureus to circumvent vancomycin killing," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    7. Alberto Signoroni & Alessandro Ferrari & Stefano Lombardi & Mattia Savardi & Stefania Fontana & Karissa Culbreath, 2023. "Hierarchical AI enables global interpretation of culture plates in the era of digital microbiology," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    8. Tianyu Wu & Min Zhou & Jingcheng Zou & Qi Chen & Feng Qian & Jürgen Kurths & Runhui Liu & Yang Tang, 2024. "AI-guided few-shot inverse design of HDP-mimicking polymers against drug-resistant bacteria," Nature Communications, Nature, vol. 15(1), pages 1-22, December.
    9. Dmitry Leshchiner & Federico Rosconi & Bharathi Sundaresh & Emily Rudmann & Luisa Maria Nieto Ramirez & Andrew T. Nishimoto & Stephen J. Wood & Bimal Jana & Noemí Buján & Kaicheng Li & Jianmin Gao & M, 2022. "A genome-wide atlas of antibiotic susceptibility targets and pathways to tolerance," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    10. Chenyuan Wang & Yushan Xia & Runming Wang & Jingru Li & Chun-Lung Chan & Richard Yi-Tsun Kao & Patrick H. Toy & Pak-Leung Ho & Hongyan Li & Hongzhe Sun, 2023. "Metallo-sideromycin as a dual functional complex for combating antimicrobial resistance," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    11. Chencheng Qin & Yi Yang & Xiaodong Wu & Long Chen & Zhaoli Liu & Lin Tang & Lai Lyu & Danlian Huang & Dongbo Wang & Chang Zhang & Xingzhong Yuan & Wen Liu & Hou Wang, 2023. "Twistedly hydrophobic basis with suitable aromatic metrics in covalent organic networks govern micropollutant decontamination," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    12. Asmalia Md-Lasim & Farah Shafawati Mohd-Taib & Mardani Abdul-Halim & Ahmad Mohiddin Mohd-Ngesom & Sheila Nathan & Shukor Md-Nor, 2021. "Leptospirosis and Coinfection: Should We Be Concerned?," IJERPH, MDPI, vol. 18(17), pages 1-17, September.
    13. Wei Li Thong & Yingxin Zhang & Ying Zhuo & Katherine J. Robins & Joanna K. Fyans & Abigail J. Herbert & Brian J. C. Law & Jason Micklefield, 2021. "Gene editing enables rapid engineering of complex antibiotic assembly lines," Nature Communications, Nature, vol. 12(1), pages 1-10, December.
    14. Zhiwen Liu & Kangli Guo & Liemei Yan & Kai Zhang & Ying Wang & Xiaokang Ding & Nana Zhao & Fu-Jian Xu, 2023. "Janus nanoparticles targeting extracellular polymeric substance achieve flexible elimination of drug-resistant biofilms," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    15. Pavan Gollapalli, 2017. "Anti-Evolutionary Targets in Bacterial Efflux Pumps Future Therapeutics to Combat Antibacterial Resistance," Current Trends in Biomedical Engineering & Biosciences, Juniper Publishers Inc., vol. 1(5), pages 109-110, February.
    16. Ifeanyi A. Onwuezobe* & Ubong E. Etang, 2018. "Current Antibiotic Resistance Trends of Uropathogens from Outpatients in a Nigerian Urban Health Care Facility," International Journal of Healthcare and Medical Sciences, Academic Research Publishing Group, vol. 4(6), pages 99-104, 06-2018.
    17. Kade D. Roberts & Yan Zhu & Mohammad A. K. Azad & Mei-Ling Han & Jiping Wang & Lynn Wang & Heidi H. Yu & Andrew S. Horne & Jo-Anne Pinson & David Rudd & Nicolas H. Voelcker & Nitin A. Patil & Jinxin Z, 2022. "A synthetic lipopeptide targeting top-priority multidrug-resistant Gram-negative pathogens," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    18. Qian Zhang & Bin Song & Yanan Xu & Yunmin Yang & Jian Ji & Wenjun Cao & Jianping Lu & Jiali Ding & Haiting Cao & Binbin Chu & Jiaxu Hong & Houyu Wang & Yao He, 2023. "In vivo bioluminescence imaging of natural bacteria within deep tissues via ATP-binding cassette sugar transporter," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    19. Zhengyan Guo & Yao Yao & Yuan-Cheng Chang, 2022. "Research on Customer Behavioral Intention of Hot Spring Resorts Based on SOR Model: The Multiple Mediation Effects of Service Climate and Employee Engagement," Sustainability, MDPI, vol. 14(14), pages 1-15, July.
    20. Jianping Li & Ampon Sae Her & Alida Besch & Belen Ramirez-Cordero & Maureen Crames & James R. Banigan & Casey Mueller & William M. Marsiglia & Yingkai Zhang & Nathaniel J. Traaseth, 2024. "Dynamics underlie the drug recognition mechanism by the efflux transporter EmrE," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50453-3. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.