IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-37749-6.html
   My bibliography  Save this article

Repurposing host-guest chemistry to sequester virulence and eradicate biofilms in multidrug resistant Pseudomonas aeruginosa and Acinetobacter baumannii

Author

Listed:
  • Christopher Jonkergouw

    (Aalto University, School of Chemical Engineering, Department of Bioproducts and Biosystems)

  • Ngong Kodiah Beyeh

    (Oakland University, Department of Chemistry
    Aalto University, School of Science, Department of Applied Physics)

  • Ekaterina Osmekhina

    (Aalto University, School of Chemical Engineering, Department of Bioproducts and Biosystems)

  • Katarzyna Leskinen

    (University of Helsinki, Translational Immunology Research Program)

  • S. Maryamdokht Taimoory

    (University of Windsor, Department of Chemistry and Biochemistry
    University of Michigan, Department of Chemistry)

  • Dmitrii Fedorov

    (Aalto University, School of Chemical Engineering, Department of Bioproducts and Biosystems)

  • Eduardo Anaya-Plaza

    (Aalto University, School of Chemical Engineering, Department of Bioproducts and Biosystems)

  • Mauri A. Kostiainen

    (Aalto University, School of Chemical Engineering, Department of Bioproducts and Biosystems)

  • John F. Trant

    (University of Windsor, Department of Chemistry and Biochemistry)

  • Robin H. A. Ras

    (Aalto University, School of Chemical Engineering, Department of Bioproducts and Biosystems
    Aalto University, School of Science, Department of Applied Physics)

  • Päivi Saavalainen

    (University of Helsinki, Translational Immunology Research Program
    Folkhälsan Research Center)

  • Markus B. Linder

    (Aalto University, School of Chemical Engineering, Department of Bioproducts and Biosystems)

Abstract

The limited diversity in targets of available antibiotic therapies has put tremendous pressure on the treatment of bacterial pathogens, where numerous resistance mechanisms that counteract their function are becoming increasingly prevalent. Here, we utilize an unconventional anti-virulence screen of host-guest interacting macrocycles, and identify a water-soluble synthetic macrocycle, Pillar[5]arene, that is non-bactericidal/bacteriostatic and has a mechanism of action that involves binding to both homoserine lactones and lipopolysaccharides, key virulence factors in Gram-negative pathogens. Pillar[5]arene is active against Top Priority carbapenem- and third/fourth-generation cephalosporin-resistant Pseudomonas aeruginosa and Acinetobacter baumannii, suppressing toxins and biofilms and increasing the penetration and efficacy of standard-of-care antibiotics in combined administrations. The binding of homoserine lactones and lipopolysaccharides also sequesters their direct effects as toxins on eukaryotic membranes, neutralizing key tools that promote bacterial colonization and impede immune defenses, both in vitro and in vivo. Pillar[5]arene evades both existing antibiotic resistance mechanisms, as well as the build-up of rapid tolerance/resistance. The versatility of macrocyclic host-guest chemistry provides ample strategies for tailored targeting of virulence in a wide range of Gram-negative infectious diseases.

Suggested Citation

  • Christopher Jonkergouw & Ngong Kodiah Beyeh & Ekaterina Osmekhina & Katarzyna Leskinen & S. Maryamdokht Taimoory & Dmitrii Fedorov & Eduardo Anaya-Plaza & Mauri A. Kostiainen & John F. Trant & Robin H, 2023. "Repurposing host-guest chemistry to sequester virulence and eradicate biofilms in multidrug resistant Pseudomonas aeruginosa and Acinetobacter baumannii," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37749-6
    DOI: 10.1038/s41467-023-37749-6
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-37749-6
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-023-37749-6?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. Anatol Luther & Matthias Urfer & Michael Zahn & Maik Müller & Shuang-Yan Wang & Milon Mondal & Alessandra Vitale & Jean-Baptiste Hartmann & Timothy Sharpe & Fabio Lo Monte & Harsha Kocherla & Elizabet, 2019. "Author Correction: Chimeric peptidomimetic antibiotics against Gram-negative bacteria," Nature, Nature, vol. 576(7786), pages 5-5, December.
    2. Yu Imai & Kirsten J. Meyer & Akira Iinishi & Quentin Favre-Godal & Robert Green & Sylvie Manuse & Mariaelena Caboni & Miho Mori & Samantha Niles & Meghan Ghiglieri & Chandrashekhar Honrao & Xiaoyu Ma , 2019. "A new antibiotic selectively kills Gram-negative pathogens," Nature, Nature, vol. 576(7787), pages 459-464, December.
    3. Yong-Xin Li & Zheng Zhong & Wei-Peng Zhang & Pei-Yuan Qian, 2018. "Discovery of cationic nonribosomal peptides as Gram-negative antibiotics through global genome mining," Nature Communications, Nature, vol. 9(1), pages 1-9, December.
    4. Anatol Luther & Matthias Urfer & Michael Zahn & Maik Müller & Shuang-Yan Wang & Milon Mondal & Alessandra Vitale & Jean-Baptiste Hartmann & Timothy Sharpe & Fabio Lo Monte & Harsha Kocherla & Elizabet, 2019. "Chimeric peptidomimetic antibiotics against Gram-negative bacteria," Nature, Nature, vol. 576(7787), pages 452-458, December.
    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. Runrun Wu & Jeremy W. Bakelar & Karl Lundquist & Zijian Zhang & Katie M. Kuo & David Ryoo & Yui Tik Pang & Chen Sun & Tommi White & Thomas Klose & Wen Jiang & James C. Gumbart & Nicholas Noinaj, 2021. "Plasticity within the barrel domain of BamA mediates a hybrid-barrel mechanism by BAM," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    2. Parthasarathi Rath & Adrian Hermann & Ramona Schaefer & Elia Agustoni & Jean-Marie Vonach & Martin Siegrist & Christian Miscenic & Andreas Tschumi & Doris Roth & Christoph Bieniossek & Sebastian Hille, 2023. "High-throughput screening of BAM inhibitors in native membrane environment," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    3. Christopher J. Barden & Fan Wu & J. Pedro Fernandez-Murray & Erhu Lu & Shengguo Sun & Marcia M. Taylor & Annette L. Rushton & Jason Williams & Mahtab Tavasoli & Autumn Meek & Alla Siva Reddy & Lisa M., 2024. "Computer-aided drug design to generate a unique antibiotic family," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    4. Zhuo Cheng & Bei-Bei He & Kangfan Lei & Ying Gao & Yuqi Shi & Zheng Zhong & Hongyan Liu & Runze Liu & Haili Zhang & Song Wu & Wenxuan Zhang & Xiaoyu Tang & Yong-Xin Li, 2024. "Rule-based omics mining reveals antimicrobial macrocyclic peptides against drug-resistant clinical isolates," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    5. Dawei Sun & Kelly M. Storek & Dimitry Tegunov & Ying Yang & Christopher P. Arthur & Matthew Johnson & John G. Quinn & Weijing Liu & Guanghui Han & Hany S. Girgis & Mary Kate Alexander & Austin K. Murc, 2024. "The discovery and structural basis of two distinct state-dependent inhibitors of BamA," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    6. Mathieu Botte & Dongchun Ni & Stephan Schenck & Iwan Zimmermann & Mohamed Chami & Nicolas Bocquet & Pascal Egloff & Denis Bucher & Matilde Trabuco & Robert K. Y. Cheng & Janine D. Brunner & Markus A. , 2022. "Cryo-EM structures of a LptDE transporter in complex with Pro-macrobodies offer insight into lipopolysaccharide translocation," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    7. Yunmin Yang & Binbin Chu & Jiayi Cheng & Jiali Tang & Bin Song & Houyu Wang & Yao He, 2022. "Bacteria eat nanoprobes for aggregation-enhanced imaging and killing diverse microorganisms," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    8. Xinghong Zhao & Xinyi Zhong & Shinong Yang & Jiarong Deng & Kai Deng & Zhengqun Huang & Yuanfeng Li & Zhongqiong Yin & Yong Liu & Jakob H. Viel & Hongping Wan, 2024. "Guiding antibiotics towards their target using bacteriophage proteins," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    9. 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.
    10. Katherine L. Fenn & Jim E. Horne & Joel A. Crossley & Nils Böhringer & Romany J. Horne & Till F. Schäberle & Antonio N. Calabrese & Sheena E. Radford & Neil A. Ranson, 2024. "Outer membrane protein assembly mediated by BAM-SurA complexes," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    11. Kerry R. Buchholz & Mike Reichelt & Matthew C. Johnson & Sarah J. Robinson & Peter A. Smith & Steven T. Rutherford & John G. Quinn, 2024. "Potent activity of polymyxin B is associated with long-lived super-stoichiometric accumulation mediated by weak-affinity binding to lipid A," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    12. Yuqing Li & Yeying Ma & Yinzheng Xia & Tao Zhang & Shuaishuai Sun & Jiangtao Gao & Hongwei Yao & Huan Wang, 2023. "Discovery and biosynthesis of tricyclic copper-binding ribosomal peptides containing histidine-to-butyrine crosslinks," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    13. Shan Wang & Sixing Lin & Qing Fang & Roland Gyampoh & Zhou Lu & Yingli Gao & David J. Clarke & Kewen Wu & Laurent Trembleau & Yi Yu & Kwaku Kyeremeh & Bruce F. Milne & Jioji Tabudravu & Hai Deng, 2022. "A ribosomally synthesised and post-translationally modified peptide containing a β-enamino acid and a macrocyclic motif," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    14. Zhenyan Zhang & Qi Zhang & Tingzhang Wang & Nuohan Xu & Tao Lu & Wenjie Hong & Josep Penuelas & Michael Gillings & Meixia Wang & Wenwen Gao & Haifeng Qian, 2022. "Assessment of global health risk of antibiotic resistance genes," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    15. Xu Wang & Sarah B. Nyenhuis & Harris D. Bernstein, 2024. "The translocation assembly module (TAM) catalyzes the assembly of bacterial outer membrane proteins in vitro," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    16. Jiekai Sun & Xu Wang & Ye Gao & Shuangyu Li & Ziwei Hu & Yan Huang & Baoqiang Fan & Xia Wang & Miao Liu & Chunhua Qiao & Wei Zhang & Yipeng Wang & Xingyue Ji, 2024. "H2S scavenger as a broad-spectrum strategy to deplete bacteria-derived H2S for antibacterial sensitization," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    17. Sijia Guo & Shu Wang & Suze Ma & Zixin Deng & Wei Ding & Qi Zhang, 2022. "Radical SAM-dependent ether crosslink in daropeptide biosynthesis," Nature Communications, Nature, vol. 13(1), pages 1-9, December.
    18. Ruihuan Yang & Qing Shi & Tingting Huang & Yichao Yan & Shengzhang Li & Yuan Fang & Ying Li & Linlin Liu & Longyu Liu & Xiaozheng Wang & Yongzheng Peng & Jiangbo Fan & Lifang Zou & Shuangjun Lin & Gon, 2023. "The natural pyrazolotriazine pseudoiodinine from Pseudomonas mosselii 923 inhibits plant bacterial and fungal pathogens," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    19. Ana Teresa López-Jiménez & Serge Mostowy, 2021. "Emerging technologies and infection models in cellular microbiology," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    20. Bob Schiffrin & Joel A. Crossley & Martin Walko & Jonathan M. Machin & G. Nasir Khan & Iain W. Manfield & Andrew J. Wilson & David J. Brockwell & Tomas Fessl & Antonio N. Calabrese & Sheena E. Radford, 2024. "Dual client binding sites in the ATP-independent chaperone SurA," Nature Communications, Nature, vol. 15(1), pages 1-16, 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:14:y:2023:i:1:d:10.1038_s41467-023-37749-6. 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.